Pyrazolo[1,5-a]pyrazin-4-yl derivatives

ABSTRACT

A compound compound having the structure: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein A, A′ and A″ are independently O, C═O, C—R′ or N—R″, where R′ and R″ may independently be H, amino, —NR 7 COR 6 , COR 6 , —CONR 7 R 8 , C 1 -C 6  alkyl, or hydroxy(C 1 -C 6  alkyl), and R″ may be present or absent, and is present where the rules of valency permit, and where not more than one of A, A′ and A″ is O or C═O; R 0  and R are independently H, Br, Cl, F, or C 1 -C 6  alkyl; R 1  is H, C 1 -C 6  alkyl, or hydroxy(C 1 -C 6  alkyl); R 2  is selected from the group consisting of H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy(C 1 -C 6  alkyl), phenyl(C 1 -C 6  alkyl), formyl, heteroaryl, heterocyclic, —COR 6 , —OCOR 6 , —COOR 6 , —NR 7 COR 6 , —CONR 7 R 8 , and —(CH 2 ) n —W, where W is cyano, hydroxy, C 3 -C 8  cycloalkyl, —SO 2 NR 7 R 8 , and —SO 2 —R 9 , where R 9  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C 1 -C 6  alkyl; X is C—R 3  or N, where R 3  may be H or C 1 -C 6  alkyl; R 4  and R 5  are independently H, amino, C 1 -C 6  alkyl, or hydroxy(C 1 -C 6  alkyl); R 6 , R 7  and R 8  are each independently H, C 1 -C 6  alkyl, C 1 -C 4  alkoxy(C 1 -C 6  alkyl), or C 3 -C 8  cycloalkyl, said C 1 -C 6  alkyl is optionally substituted by halo, CN or hydroxy; or, R 7  and R 8  together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C 1 -C 6  alkyl; and, n is 0, 1, 2 or 3. Also provided are methods of treatment as Janus Kinase inhibitors and pharmaceutical compositions containing the compounds of the invention and combinations thereof with other therapeutic agents.

FIELD OF THE INVENTION

The present invention provides pharmaceutically activepyrazolo[1,5-a]pyrazin-4-yl TYK2 ligands and analogues. Such compoundsare useful for inhibiting Janus Kinases (JAKs). This invention also isdirected to compositions comprising methods for making such compounds,and methods for treating and preventing conditions mediated by JAK.

BACKGROUND OF THE INVENTION

Protein kinases are families of enzymes that catalyze thephosphorylation of specific residues in proteins, broadly classifiedinto tyrosine and serine/threonine kinases. Inappropriate kinaseactivity, arising from mutation, over-expression, or inappropriateregulation, dys-regulation or de-regulation, as well as over- orunder-production of growth factors or cytokines has been implicated inmany diseases, including but not limited to cancer, cardiovasculardiseases, allergies, asthma and other respiratory diseases, autoimmunediseases, inflammatory diseases, bone diseases, metabolic disorders, andneurological and neurodegenerative disorders such as Alzheimer'sdisease. Inappropriate kinase activity triggers a variety of biologicalcellular responses relating to cell growth, cell differentiation, cellfunction, survival, apoptosis, and cell mobility implicated in theaforementioned and related diseases.

Thus, protein kinases have emerged as an important class of enzymes astargets for therapeutic intervention. In particular, the JAK family ofcellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) play acentral role in cytokine signaling (Kisseleva et al., Gene, 2002, 285,1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to theirreceptors, cytokines activate JAK which then phosphorylate the cytokinereceptor, thereby creating docking sites for signaling molecules,notably, members of the signal transducer and activator of transcription(STAT) family that ultimately lead to gene expression. Numerouscytokines are known to activate the JAK family. These cytokines include,the interferon (IFN) family (IFN-alpha, IFN-beta, IFN-omega, Limitin,IFN-gamma, IL-10, IL-19, IL-20, IL-22), the gp130 family (IL-6, IL-11,OSM, LIF, CNTF, NNT-1/BSF-3, G-CSF, CT-1, Leptin, IL-12, IL-23), gamma Cfamily (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 family(IL-3, IL-5, GM-CSF), single chain family (EPO, GH, PRL, TPO), receptortyrosine kinases (EGF, PDGF, CSF-1, HGF), and G-protein coupledreceptors (AT1).

There remains a need for new compounds that effectively and selectivelyinhibit specific JAK enzymes: TYK2 in particular. TYK2 is a JAK kinasefamily member, and is important in the signaling of the type Iinterferons (including IFNalpha, INFbeta), IL-6, IL-10, IL-12 and IL-23(Liang, Y. et al., Expert Opinion on Therapeutic Targets, 18, 5, 571-580(2014)). As such, TYK2 signals with other members of the JAK kinasefamily in the following combinations: TYK2/JAK1, TYK2/JAK2,TYK2/JAK1/JAK2. TYK2 has been shown to be important in thedifferentiation and function of multiple cell types important ininflammatory disease and autoimmune disease including natural killercells, B cells, and T helper cell types. Aberrant TYK2 expression isassociated with multiple autoimmune or inflammatory conditions.Modulation of immune activity through inhibition of TYK2 kinase activitycan prove useful in the treatment of various immune disorders (O'Shea JJ, Plenge R, Immunity, 36, 542-50 (2012); Murray, P. J., J. Immunol.,178, 2623-2629 (2007); Kisseleva, T., et al., Gene, 285, 1-24 (2002))while avoiding JAK2 dependent erythropoietin (EPO) and thrombopoietin(TPO) signaling (Neubauer H., et al., Cell, 93(3), 397-409 (1998);Parganas E., et al., Cell, 93(3), 385-95 (1998)).

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I having thestructure:

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A, A′ and A″ are independently 0, C═O, C—R′ or N—R″, where R′and R″ may independently be H, amino, —NR₇COR₆, COR⁶, —CONR₇R₈, C₁-C₆alkyl, or hydroxy(C₁-C₆ alkyl), and R″ may be present or absent, and ispresent where the rules of valency permit, and where not more than oneof A, A′ and A″ is O or C═O; R₀ and R are independently H, Br, Cl, F, orC₁-C₆ alkyl; R₁ is H, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl); R₂ isselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ alkoxy,hydroxy(C₁-C₆ alkyl), phenyl(C₁-C₆ alkyl), formyl, heteroaryl,heterocyclic, —COR₆, —OCOR₆, —COOR₆, —NR₇COR₆, —CONR₇R₈, and—(CH₂)_(n)—W, where W is cyano, hydroxy, C₃-C₈ cycloalkyl, —SO₂NR₇R₈,and —SO₂—R₉, where R₉ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, heteroaryl, orheterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, orheteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy,or C₁-C₆ alkyl; X is C—R₃ or N, where R₃ may be H or C₁-C₆ alkyl; R₄ andR₅ are independently H, amino, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl); R₆,R₇ and R₈ are each independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy(C₁-C₆alkyl), or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionally substitutedby halo, CN or hydroxy; or, R₇ and R₈ together with the atom bondedthereto form a 5- or 6-membered ring, said ring being optionallysubstituted by halo, hydroxy, CN, or C₁-C₆ alkyl; and, n is 0, 1, 2 or3.

In other aspects, the present invention also provides:

pharmaceutical compositions which comprise a pharmaceutically acceptablecarrier and a compound of formula I;

methods for treating conditions or disorders including inflammation,autoimmune disease, systemic lupus erythematous, lupus nephritis,discoid lupus, cutaneous lupus, central nervous system lupus, rheumatoidarthritis, psoriatic arthritis, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, asthma, allergic asthma, Type I diabetes,polymyositis, dermatomyositis, type I interferonopathies includingAicardiGoutieres syndrome and other mendelian diseases of overexpressionof type I interferon, multiple sclerosis, primary progressive multiplesclerosis, relapsing remitting multiple sclerosis, primary biliarycirrhosis also known as primary biliary cholangitis, primary sclerosingcholangitis, autoimmune hepatitis, non-alcoholic fatty liver disease,non-alcoholic steatohepatitis, psoriasis, dermatomyositis, scleroderma,atopic dermatitis, vitiligo, alopecia areata, spondylopathy, ankylosingspondylitis, Alzheimer's disease, neuro-inflammation myositis,vasculitis, pemphigus, Crohn's disease, lupus, nephritis, psoriasis,multiple sclerosis, major depression disorder, allergy, asthma,Sjogren's disease, dry eye syndrome, transplant rejection, cancer,inflammatory bowel disease, septic shock, cardiopulmonary dysfunction,vitiligo, alopecia, acute respiratory disease, ankylosing spondylitis,autoimmune hepatitis, primary sclerosing cholangitis, primary biliarycirrhosis, Alzheimer's disease, or cachexia by administering to asubject in need a therapeutically effective amount of a compound offormula I or a pharmaceutically acceptable salt thereof;

Methods for treating conditions or disorders including atopicdermatitis, eczema, psoriasis, scleroderma, lupus, pruritus, fatigue,other pruritic conditions, allergic reactions including allergicdermatitis in mammal, horse allergic diseases including bitehypersensitivity, summer eczema, sweet itch in horses, heaves,inflammatory airway disease, recurrent airway obstruction, airwayhyper-responsiveness, and chronic obstruction pulmonary disease byadministering to a mammal in need a therapeutically effective amount ofa compound of formula I, or a pharmaceutically acceptable salt thereof;and, methods for the preparation of compounds of the present invention.

The present invention will be further understood from the followingdescription given by way of example only. The present invention isdirected to a class of pyrazolo[1,5-a]pyrazin-4-yl derivatives. Inparticular, the present invention is directed topyrazolo[1,5-a]pyrazin-4-yl compounds useful as inhibitors of JAKs, andparticularly TYK2. While the present invention is not so limited, anappreciation of various aspects of the invention will be gained throughthe following discussion and the examples.

The term “alkyl”, alone or in combination, means an acyclic, saturatedhydrocarbon group of the formula C_(n)H_(2n+1) which may be linear orbranched. Examples of such groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyland hexyl. Unless otherwise specified, an alkyl group comprises from 1to 6 carbon atoms. The carbon atom content of alkyl and various otherhydrocarbon-containing moieties is indicated by a prefix designating alower and upper number of carbon atoms in the moiety, that is, theprefix C_(i)-C_(j), indicates a moiety of the integer “i” to the integer“j” carbon atoms, inclusive. Thus, for example, C₁-C₆ alkyl refers toalkyl of one to six carbon atoms, inclusive.

The term “hydroxy,” as used herein, means an OH group. The term“heterocyclic” refers to a saturated or partially saturated (i.e., nonaromatic) heterocycle which contains three to ten ring atoms where oneor more, preferably, one, two or three ring atoms, are heteratom(s)selected from N, O and S, the remaining being carbon, and which may beattached via a ring nitrogen atom or a ring carbon atom. Equally, whensubstituted, the substituent may be located on a ring nitrogen atom (ifthe substituent is joined through a carbon atom) or a ring carbon atom(in all cases). Specific examples include oxiranyl, aziridinyl,oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, piperazinyl,azepanyl, oxepanyl, oxazepanyl and diazepinyl.

The term “aryl” refers to an aromatic monocyclic or bicyclic hydrocarboncontaining six to ten ring carbon atoms which may be attached via one ofthe ring carbon atoms. Equally, when substituted, the substituent may belocated on a ring carbon atom. Specific examples include, but are notlimited to, phenyl, tolyl, xylyl, trimethylphenyl, and naphthyl.Examples of aryl substituents include, but are not limited to, alkyl,hydroxyl, halo, nitrile, alkoxy, trifluoromethyl, carboxamido, SO₂Me,benzyl, and substituted benzyl.

The term “heteroaryl” refers to a monovalent aromatic monocyclic orbicyclic heterocycle of five to ten ring atoms where one or more,preferably, one, two or three ring atoms, are heteratom(s) selected fromN, O, and S, the remaining being carbon, and which may be attached via aring carbon atom or a ring nitrogen atom with an appropriate valency.Equally, when substituted, the substituent may be located on a ringcarbon atom or a ring nitrogen atom with an appropriate valency.Specific examples include, but are not limited to, thienyl, furanyl,pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl,pyridazinyl, pyrimidinyl and pyrazinyl. The term “cycloalkyl” means amonocyclic, saturated hydrocarbon group of the formula C_(n)H_(2n−1).Examples include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specified, acycloalkyl group comprises from 3 to 8 carbon atoms.

The terms “halo” and “halogen” refer to fluoride (F), chloride (Cl),bromide (Br) or iodide (I).

The term “mammal” refers to human, livestock or companion animals.

The term “companion animal” or “companion animals” refers to animalskept as pets or household animal. Examples of companion animals includedogs, cats, and rodents including hamsters, guinea pigs, gerbils and thelike, rabbits, ferrets and birds.

The term “livestock” refers to animals reared or raised in anagricultural setting to make products such as food or fiber, or for itslabor. In some embodiments, livestock are suitable for consumption bymammals, for example humans. Examples of livestock animals includecattle, goats, horses, pigs, sheep, including lambs, and rabbits, aswell as birds, such as chickens, ducks and turkeys.

The term “treating” or “treatment” means an alleviation of symptomsassociated with a disease, disorder or condition, or halt of furtherprogression or worsening of those symptoms. Depending on the disease andcondition of the patient, the term “treatment” as used herein mayinclude one or more of curative, palliative and prophylactic treatment.Treatment can also include administering a pharmaceutical formulation ofthe present invention in combination with other therapies.

The term “therapeutically-effective” indicates the capability of anagent to prevent, or improve the severity of, the disorder. The phrase“therapeutically-effective” is to be understood to be equivalent to thephrase “effective for the treatment, prevention, or amelioration”, andboth are intended to qualify the amount of an agent—which will achievethe goal of improvement in the severity of cancer, cardiovasculardisease, or pain and inflammation and the frequency of incidence overtreatment of each agent by itself.

“Pharmaceutically acceptable” means suitable for use in mammals,companion animals or livestock animals.

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other. Eachsubstituent therefore may be identical to or different from the othersubstituent(s).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is related to novel compounds which are TYK2modulators useful for the treatment of diseases and conditionsassociated with dysregulation of TYK2. The present invention furtherprovides pharmaceutical compositions comprising such JAK enzymemodulators as well as methods of treating and/or preventing suchdiseases and conditions. Accordingly, the present invention provides acompound of formula I as represented above having the structure (I):

The invention also provides a compound having the structure (Ia):

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A, A′ and A″ are independently O, C═O, C—R′ or N—R″, where R′and R″ may independently be H, amino, —NR₇COR₆, COR⁶, —CONR₇R₈, C₁-C₆alkyl-, or hydroxy(C₁-C₆ alkyl)-, and R″ may be present or absent, andis present where the rules of valency permit, and where not more thanone of A, A′ and A″ is O or C═O; R₀ and R are independently H, Br, Cl,F, or C₁-C₆ alkyl; R₁ is H, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl)-; R₂ isselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ alkoxy-,hydroxy(C₁-C₆ alkyl)-, phenyl(C₁-C₆ alkyl)-, formyl, heteroaryl,heterocyclic, —COR₆, —OCOR₆, —COOR₆, —NR₇COR₆, —CONR₇R₈, and—(CH₂)_(n)—W, where W is cyano, hydroxy, C₃-C₈ cycloalkyl, —SO₂NR₇R₈,and —SO₂—R₉, where R₉ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, heteroaryl, orheterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, orheteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy,or C₁-C₆ alkyl; R₃ may be H or C₁-C₆ alkyl; R₄ and R₅ are independentlyH, amino, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl); R₆, R₇ and R₈ are eachindependently H, C₁-C₆ alkyl, C₁-C₄ alkoxy(C₁-C₆ alkyl), or C₃-C₈cycloalkyl, said C₁-C₆ alkyl is optionally substituted by halo, CN orhydroxy; or, R₇ and R₈ together with the atom bonded thereto form a 5-or 6-membered ring, said ring being optionally substituted by halo,hydroxy, CN, or C₁-C₆ alkyl; and, n is 0, 1, 2 or 3.

The invention further provides a compound having the structure (Ib):

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: R″ is H, —COR₆, —CONR₇R₈, C₁-C₆ alkyl-, or hydroxy(C₁-C₆alkyl)-; R₀ and R are independently H, Br, Cl, F, or C₁-C₆ alkyl; R₁ isH, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl); R₂ is selected from the groupconsisting of H, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy(C₁-C₆ alkyl),phenyl(C₁-C₆ alkyl), formyl, heteroaryl, heterocyclic, —COR₆, —OCOR₆,—COOR₆, —NR₇COR₆, —CONR₇R₈, and —(CH₂)_(n)—W, where W is cyano, hydroxy,C₃-C₈ cycloalkyl, —SO₂NR₇R₈, and —SO₂—R₉, where R₉ is C₁-C₆ alkyl, C₃-C₈cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl,cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted orsubstituted by halo, cyano, hydroxy, or C₁-C₆ alkyl; R₃ may be H orC₁-C₆ alkyl; R₅ is H, amino, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl); R₆,R₇ and R₈ are each independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy(C₁-C₆alkyl), or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionally substitutedby halo, CN or hydroxy; or, R₇ and R₈ together with the atom bondedthereto form a 5- or 6-membered ring, said ring being optionallysubstituted by halo, hydroxy, CN, or C₁-C₆ alkyl; and, n is 0, 1, 2 or3.

The invention also provides a compound having the structure (Ic):

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: R″ is H, —COR₆, —CONR₇R₈, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl);R₂ is selected from the group consisting of H, C₁-C₆ alkyl-, C₁-C₆alkoxy-, hydroxy(C₁-C₆ alkyl)-, phenyl(C₁-C₆ alkyl)-, formyl,heteroaryl, heterocyclic, —COR₆, —OCOR₆, —COOR₆, —NR₇COR₆, —CONR₇R₈, and—(CH₂)_(n)—W, where W is cyano, hydroxy, C₃-C₈ cycloalkyl, —SO₂NR₇R₈,and —SO₂—R₉, where R₉ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, heteroaryl, orheterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, orheteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy,or C₁-C₆ alkyl; R₃ is H or C₁-C₆ alkyl; R₅ is H, amino, C₁-C₆ alkyl-, orhydroxy(C₁-C₆ alkyl)-; R₆, R₇ and R₈ are each are each independently H,C₁-C₆ alkyl-, C₁-C₄ alkoxy(C₁-C₆ alkyl)-, or C₃-C₈ cycloalkyl, saidC₁-C₆ alkyl is optionally substituted by halo, CN or hydroxy; or, R₇ andR₈ together with the atom bonded thereto form a 5- or 6-membered ring,said ring being optionally substituted by halo, hydroxy, CN, or C₁-C₆alkyl; and, n is 1, 2 or 3. In a particular embodiment, the inventionprovides said compound wherein R″ is C₁-C₆ alkyl and R₅ is H.

The invention also provides a compound having the structure (Id):

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: R″ is H, —COR₆, —CONR₇R₈, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl);R₂ is selected from the group consisting of H, 1-C₆ alkyl, 1-C₆ alkoxy,hydroxy(C₁-C₆ alkyl), phenyl(C₁-C₆ alkyl), formyl, heteroaryl,heterocyclic, —COR₆, —OCOR₆, —COOR₆, —NR₇COR₆, —CONR₇R₈, and—(CH₂)_(n)—W, where W is cyano, hydroxy, C₃-C₈ cycloalkyl, —SO₂NR₇R₈,and —SO₂—R₉, where R₉ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, heteroaryl, orheterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, orheteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy,or C₁-C₆ alkyl; R₅ is H, amino, C₁-C₆ alkyl-, or hydroxy(C₁-C₆ alkyl)-;R₆, R₇ and R₈ are each independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy(C₁-C₆alkyl), or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionally substitutedby halo, CN or hydroxy; or, R₇ and R₈ together with the atom bondedthereto form a 5- or 6-membered ring, said ring being optionallysubstituted by halo, hydroxy, CN, or C₁-C₆ alkyl; and, n is 1, 2 or 3.In a particular embodiment, the invention provides said compound whereinR″ is C₁-C₆ alkyl and R₅ is H.

The invention also provides a compound having the structure (le):

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: R₂ is selected from the group consisting of H, C₁-C₆ alkyl-,C₁-C₆ alkoxy-, hydroxy(C₁-C₆ alkyl)-, phenyl(C₁-C₆ alkyl)-, formyl,heteroaryl, heterocyclic, —COR⁸, —OCOR⁶, —COOR⁶, —CONR⁷R⁸, and—(CH₂)_(n)—W, where W is cyano, hydroxy, C₃-C₈ cycloalkyl, —SO₂NR⁷R⁸,and —SO₂—R′, where R′ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, heteroaryl, orheterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, orheteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy,or C₁-C₆ alkyl; R₆, R₇ and R₈ are each are each independently H, C₁-C₆alkyl-, C₁-C₄ alkoxy(C₁-C₆ alkyl)- or C₃-C₈ cycloalkyl said C₁-C₆ alkylis optionally substituted by halo, CN or hydroxy; or, R₇ and R₈ togetherwith the atom bonded thereto form a 5- or 6-membered ring, said ringbeing optionally substituted by halo, hydroxy, CN, or C₁-C₆ alkyl; and,n is 1, 2 or 3. In a particular embodiment, the invention provides saidcompound wherein R₂ is —(CH₂)_(n)—W, where W is cyano and n is 1, 2 or3.

The invention also provides a compound having the structure (If):

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: R″ is H, —COR₆, —CONR₇R₈, C₁-C₆ alkyl-, or hydroxy(C₁-C₆alkyl)-; R₅ is H, amino, C₁-C₆ alkyl-, or hydroxy(C₁-C₆ alkyl)-; R₆, R₇and R₈ are each are each independently H, C₁-C₆ alkyl-, C₁-C₄alkoxy(C₁-C₆ alkyl)-, or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl isoptionally substituted by halo, CN or hydroxy; or, R₇ and R₈ togetherwith the atom bonded thereto form a 5- or 6-membered ring, said ringbeing optionally substituted by halo, hydroxy, CN, or C₁-C₆ alkyl; and,n is 0, 1, 2 or 3. In a particular embodiment, the invention providessaid compound wherein R″ is C₁-C₆ alkyl. In another particularembodiment, the invention provides said compound wherein R″ is methyl.

In certain preferred embodiments, the invention provides a compoundselected from the group consisting of:

-   (1r,3r)-3-(4-(6-(3-amino-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile;-   2,2′-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1,3-diyl)diacetonitrile;-   2-((1s,3r)-1-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile;-   5-(4-(1-((1s,3r)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazole-3-carboxamide;-   (1s,3s)-3-(cyanomethyl)-3-(4-(6-(5-(hydroxymethyl)isoxazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile;-   (1r,3s)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile;-   (1s,3s)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile;-   (1r,3r)-3-(cyanomethyl)-3-(4-(3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile;-   2-((1r,    3s)-1-(4-(6-(3-amino-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile;-   (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-(hydroxymethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile;    and,-   2-(1-ethyl-3-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile,    or, a pharmaceutically acceptable salt thereof.

In a certain embodiment, the invention provides a compound which is(1r,3r)-3-(4-(6-(3-amino-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclo-butane-1-carbonitrile,or a pharmaceutically acceptable salt thereof.

In a certain embodiment, the invention provides a compound which is2,2′-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1,3-diyl)diacetonitrile,or a pharmaceutically acceptable salt thereof.

In a certain embodiment, the invention provides a compound which is2-((1s,3r)-1-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclo-butyl)acetonitrile,or a pharmaceutically acceptable salt thereof.

In a certain embodiment, the invention provides a compound which is5-(4-(1-((1s,3r)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazole-3-carboxamide,or a pharmaceutically acceptable salt thereof.

In a certain embodiment, the invention provides a compound which is(1s,3s)-3-(cyanomethyl)-3-(4-(6-(5-(hydroxymethyl)isoxazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile,or a pharmaceutically acceptable salt thereof.

In a certain embodiment, the invention provides a compound which is(1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile,or a pharmaceutically acceptable salt thereof.

In another certain embodiment, the invention provides a compound whichis(1s,3s)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile,or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the invention provides a compound which is(1r,3r)-3-(cyanomethyl)-3-(4-(3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile,or a pharmaceutically acceptable salt thereof.

In a certain other embodiment, the invention provides a compound whichis2-((1r,3s)-1-(4-(6-(3-amino-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile,or a pharmaceutically acceptable salt thereof.

In another certain embodiment, the invention provides a compound whichis2-(1-ethyl-3-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile,or, a pharmaceutically acceptable salt thereof.

The invention further provides a pharmaceutical or a veterinarycomposition comprising a compound of formula I and Ia-f or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The invention also provides a method of treating a disease or conditionfor which a Tyk2 inhibitor is indicated, in a subject in need of suchtreatment, comprising administering to the subject a therapeuticallyeffective amount of a compound of formula I or Ia-f, or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or salt.

The invention also provides a method for treating or preventing adisorder or condition selected from allergic rhinitis, nasal congestion,rhinorrhea, perennial rhinitis, nasal inflammation, asthma of all types,chronic obstructive pulmonary disease, chronic or acutebronchoconstriction, chronic bronchitis, small airways obstruction,emphysema, chronic eosinophilic pneumonia, adult respiratory distresssyndrome, exacerbation of airways hyper-reactivity consequent to otherdrug therapy, pulmonary vascular disease, pulmonary arterialhypertension, acute lung injury, bronchiectasis, sinusitis, allergicconjunctivitis, idiopathic pulmonary fibrosis or atopic dermatitis,comprising administering to the subject a therapeutically effectiveamount of a compound of formula I and Ia-f, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvate ofsaid compound or salt.

The invention also provides a method of treating primary biliarycirrhosis comprising administering to the subject a therapeuticallyeffective amount of a compound of formula I or Ia-f, or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or salt.

The invention also provides a method of treating a disease or conditionselected from inflammation, inflammation, autoimmune disease, systemiclupus erythematous, lupus nephritis, discoid lupus, cutaneous lupus,central nervous system lupus, rheumatoid arthritis, psoriatic arthritis,inflammatory bowel disease, Crohn's disease, ulcerative colitis, asthma,allergic asthma, Type I diabetes, polymyositis, dermatomyositis, type Iinterferonopathies including Aicardi-Goutières syndrome and othermendelian diseases of overexpression of type I interferon, multiplesclerosis, primary progressive multiple sclerosis, relapsing remittingmultiple sclerosis, primary biliary cirrhosis also known as primarybiliary cholangitis, primary sclerosing cholangitis, autoimmunehepatitis, non-alcoholic fatty liver disease, non-alcoholicsteatohepatitis, psoriasis, dermatomyositis, scleroderma, atopicdermatitis, vitiligo, alopecia areata, spondylopathy, ankylosingspondylitis, Alzheimer's disease, neuro-inflammation comprisingadministering to the subject a therapeutically effective amount of acompound of formula I or Ia-f, or a pharmaceutically acceptable saltthereof, or a pharmaceutically acceptable solvate of said compound orsalt.

The invention also provides a method of treating the symptoms ofinflammatory or autoimmune disease, including pruritis and fatigue.

In certain embodiments, the therapeutically effective amount used inaccord with the method is from 0.01 mg/kg of body weight/day to 100mg/kg of body weight/day. In certain other embod-iments, thetherapeutically effective amount used in accord with the method iswherein the therapeutically effective amount is from 0.1 mg/kg of bodyweight/day to 10 mg/kg of body weight/day.

Compounds of the invention that have the same molecular formula butdiffer in the nature or sequence of bonding of their atoms or thearrangement of their atoms in space are termed “isomers”. Isomers thatdiffer in the arrangement of their atoms in space are termed“stereoisomers”. It will be appreciated by those skilled in the art thatthe compound of formula I can exist as cis- and trans-achiraldiastereomers.

Included within the scope of the described compounds are all isomers(e.g., cis-, trans-, or diastereomers) of the compounds described hereinalone as well as any mixtures. All of these forms, includingenantiomers, diastereomers, cis, trans, syn, anti, solvates (includinghydrates), tautomers, and mixtures thereof, are included in thedescribed compounds. Stereoisomeric mixtures, e.g., mixtures ofdiastereomers, can be separated into their corresponding isomers in aknown manner by means of suitable separation methods. Diastereomericmixtures for example may be separated into their individualdiastereomers by means of fractionated crystallization, chromatography,solvent distribution, and similar procedures. This separation may takeplace either at the level of one of the starting compounds or in acompound of formula I itself. Enantiomers may be separated through theformation of diastereomeric salts, for example by salt formation with anenantiomer-pure chiral acid, or by means of chromatography, for exampleby HPLC, using chromatographic substrates with chiral ligands. Thepresent invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula I wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Certain isotopically-labelled compounds of formula I, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e., ³H,and carbon-14, i.e., ¹⁴C, particularly useful for this purpose in viewof their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e., ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, a can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof formula I can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples and Preparations using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

In therapeutic use for treating disorders in a mammal, a compound of thepresent invention or its pharmaceutical compositions can be administeredorally, parenterally, topically, rectally, transmucosally, orintestinally. Parenteral administrations include indirect injections togenerate a systemic effect or direct injections to the afflicted area.Topical administrations include the treatment of skin or organs readilyaccessible by local application, for example, eyes or ears. It alsoincludes transdermal delivery to generate a systemic effect. The rectaladministration includes the form of suppositories. The preferred routesof administration are oral and parenteral.

Pharmaceutically acceptable salts of the compounds of formula I and Ia-finclude the acid addition and base salts thereof. Suitable acid additionsalts are formed from acids which form non-toxic salts. Examples includethe acetate, adipate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate,cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,saccharate, stearate, succinate, tannate, tartrate, tosylate,trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulfate and hemicalcium salts. For a review on suitable salts, seeHandbook of Pharmaceutical Salts: Properties, Selection, and Use byStahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of formula I and Ia-f maybe prepared, respectively, by one or more of three methods: (i) byreacting the compound of formula I and Ia-f with the desired acid orbase; (ii) by removing an acid- or base-labile protecting group from asuitable precursor of the compound of formula I and Ia-f or byring-opening a suitable cyclic precursor, for example, a lactone orlactam, using the desired acid or base; or (iii) by converting one saltof the compound of formula I or Ia-f to another by reaction with anappropriate acid or base or by means of a suitable ion exchange column.All three reactions are typically carried out in solution. The resultingsalt may precipitate out and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionization in theresulting salt may vary from completely ionized to almost non-ionized.

Pharmaceutical compositions of the present invention may be manufacturedby methods well known in the art, e.g., by means of conventional mixing,dissolving, granulation, dragee-making, levigating, emulsifying,encapsulating, entrapping, lyophilizing processes or spray drying.

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morepharmaceutically acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the active compound intopreparations, which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Pharmaceuticallyacceptable excipients and carriers are generally known to those skilledin the art and are thus included in the instant invention. Suchexcipients and carriers are described, for example, in Remington'sPharmaceutical Sciences, Mack Pub. Co., New Jersey (1991). Theformulations of the invention can be designed to be short-acting,fast-releasing, long-acting, and sustained-releasing. Thus, thepharmaceutical formulations can also be formulated for controlledrelease or for slow release.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in anamount sufficient to achieve the intended purpose, i.e., control or thetreatment of disorders or diseases. More specifically, a therapeuticallyeffective amount means an amount of compound effective to prevent,alleviate or ameliorate symptoms/signs of disease or prolong thesurvival of the subject being treated.

The quantity of active component, which is the compound of thisinvention, in the pharmaceutical composition and unit dosage formthereof, may be varied or adjusted widely depending upon the manner ofadministration, the potency of the particular compound and the desiredconcentration. Determination of a therapeutically effective amount iswell within the capability of those skilled in the art. Generally, thequantity of active component will range between 0.01% to 99% by weightof the composition.

Generally, a therapeutically effective amount of dosage of activecomponent will be in the range of about 0.01 to about 100 mg/kg of bodyweight/day, preferably about 0.1 to about 10 mg/kg of body weight/day,more preferably about 0.3 to 3 mg/kg of body weight/day, even morepreferably about 0.3 to 1.5 mg/kg of body weight/day It is to beunderstood that the dosages may vary depending upon the requirements ofeach subject and the severity of the disorders or diseases beingtreated.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

Also, it is to be understood that the initial dosage administered may beincreased beyond the above upper level in order to rapidly achieve thedesired plasma concentration. On the other hand, the initial dosage maybe smaller than the optimum and the daily dosage may be progressivelyincreased during the course of treatment depending on the particularsituation. If desired, the daily dose may also be divided into multipledoses for administration, e.g., two to four times per day.

The present invention also provides any of the uses, methods orcompositions as defined above wherein the compound of formula I or Ia-f,or a pharmaceutically acceptable salt thereof, or pharmaceuticallyacceptable solvate of said compound or salt, is used in combination withanother pharmacologically active compound, particularly one of thefunctionally-defined classes or specific compounds listed below. Theseagents may be administered as part of the same or separate dosage forms,via the same or different routes of administration, and on the same ordifferent administration schedules according to standard pharmaceuticalpractice known to one skilled in the art.

Suitable agents for use in combination therapy with a compound offormula I or Ia-f, or a pharmaceutically acceptable salt thereof, orpharmaceutically acceptable solvate of said compound or salt,sulfasalazine, mesalazine, prednisone, azathioprine, infliximab,adalimumab, belimumab, becertolizumab, natalizumab, vedolizumab,hydrocortisone, budesonide, cyclosporin, tacrolimus, fexofenadine,6-mercaptopurine, methotrexate, ursodeoxycholic acid, obeticholic acid,anti-histamines, rifampin, prednisone, methotrexate, azathioprine,cyclophosphamide, hydroxychloroquine, mofetil, sodium mycophenolate,tacrolimus, leflunomide, chloroquine and quinacrine, thalidomide,rituxan, NSAIDs, solumedrol, depomedrol and dexamethasone.

Other suitable agents for use in combination therapy with a compound offormula I or Ia-f, or a pharmaceutically acceptable salt thereof, orpharmaceutically acceptable solvate of said compound or salt, include: a5-lipoxygenase activating protein (FLAP) antagonist; a leukotrieneantagonist (LTRA) such as an antagonist of LTB₄, LTC₄, LTD₄, LTE₄,CysLT₁ or CysLT₂, e.g., montelukast or zafirlukast; a histamine receptorantagonist, such as a histamine type 1 receptor antagonist or ahistamine type 2 receptor antagonist, e.g., loratidine, fexofenadine,desloratidine, levocetirizine, methapyrilene or cetirizine; anal-adrenoceptor agonist or an α2-adrenoceptor agonist, e.g.,phenylephrine, methoxamine, oxymetazoline or methylnorephrine; amuscarinic M3 receptor antagonist, e.g. tiotropium or ipratropium; adual muscarinic M3 receptor antagononist/β2 agonist; a PDE inhibitor,such as a PDE3 inhibitor, a PDE4 inhibitor or a PDE5 inhibitor, e.g.,theophylline, sildenafil, vardenafil, tadalafil, ibudilast, cilomilastor roflumilast; sodium cromoglycate or sodium nedocromil; acyclooxygenase (COX) inhibitor, such as a non-selective inhibitor (e.g.,aspirin or ibuprofen) or a selective inhibitor (e.g. celecoxib orvaldecoxib); a glucocorticosteroid, e.g., fluticasone, mometasone,dexamethasone, prednisolone, budesonide, ciclesonide or beclamethasone;an anti-inflammatory monoclonal antibody, e.g., infliximab, adalimumab,tanezumab, ranibizumab, bevacizumab or mepolizumab; a β2 agonist, e.g.,salmeterol, albuterol, salbutamol, fenoterol or formoterol, particularlya long-acting β2 agonist; an intigrin antagonist, e.g., natalizumab; anadhesion molecule inhibitor, such as a VLA-4 antagonist; a kinin B₁ orB₂ receptor antagonist; an immunosuppressive agent, such as an inhibitorof the IgE pathway (e.g., omalizumab) or cyclosporine; a matrixmetalloprotease (MMP) inhibitor, such as an inhibitor of MMP-9 orMMP-12; a tachykinin NK₁, NK₂ or NK₃ receptor antagonist; a proteaseinhibitor, such as an inhibitor of elastase, chymase or catheopsin G; anadenosine A_(2a) receptor agonist; an adenosine A_(1b) receptorantagonist; a urokinase inhibitor; a dopamine receptor agonist (e.g.,ropinirole), particularly a dopamine D2 receptor agonist (e.g.,bromocriptine); a modulator of the NFκB pathway, such as an IKKinhibitor; a further modulator of a cytokine signalling pathway such asan inhibitor of JAK kinase, syk kinase, p38 kinase, SPHK-1 kinase, Rhokinase, EGF-R or MK-2; a mucolytic, mucokinetic or anti-tussive agent;an antibiotic; an antiviral agent; a vaccine; a chemokine; an epithelialsodium channel (ENaC) blocker or Epithelial sodium channel (ENaC)inhibitor; a nucleotide receptor agonist, such as a P2Y2 agonist; athromboxane inhibitor; niacin; a 5-lipoxygenase (5-LO) inhibitor, e.g.,Zileuton; an adhesion factor, such as VLAM, ICAM or ELAM; a CRTH2receptor (DP₂) antagonist; a prostaglandin D₂ receptor (DP₁) antagonist;a haematopoietic prostaglandin D2 synthase (HPGDS) inhibitor;interferon-β; a soluble human TNF receptor, e.g., Etanercept; a HDACinhibitor; a phosphoinositotide 3-kinase gamma (PI3Kγ) inhibitor; aphosphoinositide 3-kinase delta (PI3Kδ) inhibitor; a CXCR-1 or a CXCR-2receptor antagonist; an IRAK-4 inhibitor; and, a TLR-4 or TLR-9inhibitor, including the pharmaceutically acceptable salts of thespecifically named compounds and the pharmaceutically acceptablesolvates of said specifically named compounds and salts.

Accordingly, the invention provides methods of treating or preventing adisease, condition or disorder associated with JAK in a subject, such asa human or non-human mammal, comprising administering an effectiveamount of one or more compounds described herein to the subject.Suitable subjects that can be treated include domestic or wild animals,companion animals, such as dogs, cats, horses and the like; livestockincluding, cows and other ruminants, pigs, poultry, rabbits and thelike; primates, for example monkeys, such as rhesus monkeys andcynomolgus (also known as crab-eating or long-tailed) monkeys,marmosets, tamarins, chimpanzees, macaques and the like; and rodents,such as rats, mice, gerbils, guinea pigs and the like. In oneembodiment, the compound is administered in a pharmaceuticallyacceptable form, optionally in a pharmaceutically acceptable carrier.

Conditions in which selective targeting of the JAK pathway or modulationof the JAK kinases, particularlyTYK2, are contemplated to betherapeutically useful include, inter alia, arthritis, asthma,autoimmune diseases, cancers or tumors, diabetes, certain eye diseases,disorders or conditions, inflammation, intestinal inflammations,allergies or conditions, neurodegenerative diseases, psoriasis, andtransplant rejection. Conditions which can benefit from selectiveinhibition of TYK2 are discussed in greater detail below.

Accordingly, the compound of formula I or Ia-f or its pharmaceuticallyacceptable salts and solvates, and pharmaceutical compositions thereof,can be used to treat a variety of conditions or diseases such as thefollowing:

Arthritis, including rheumatoid arthritis, juvenile arthritis, andpsoriatic arthritis;

Autoimmune or inflammatory diseases or disorders, for exampleHashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmuneatrophic gastritis of pernicious anemia, autoimmune encephalomyelitis,autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia,sympathetic ophthalmia, myasthenia gravis, Graves' disease, primarybiliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis,chronic aggressive hepatitis, non-alcoholic fatty liver disease,non-alcoholic steatohepatitis ulcerative colitis and membranousglomerulopathy, systemic lupus erythematosis, rheumatoid arthritis,psoriatic arthritis, Sjogren's syndrome, Reiter's syndrome,polymyositis, dermatomyositis, type I interferonopathies includingAicardi-Goutières syndrome and other mendelian diseases ofoverexpression of type I interferon systemic sclerosis, polyarteritisnodosa, multiple sclerosis, relapsing remitting multiple sclerosis,primary progressive multiple sclerosis, secondary progressive multiplesclerosis, and bullous pemphigoid, and additional autoimmune diseases,which can be O-cell (humoral) based or T-cell based, including Cogan'ssyndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmunealopecia, Type I or juvenile onset diabetes, or thyroiditis;

Cancers or tumors, including alimentary/gastrointestinal tract cancer,colon cancer, liver cancer, skin cancer including mast cell tumor andsquamous cell carcinoma, breast and mammary cancer, ovarian cancer,prostate cancer, lymphoma, leukemia, including acute myelogenousleukemia and chronic myelogenous leukemia, kidney cancer, lung cancer,muscle cancer, bone cancer, bladder cancer, brain cancer, melanomaincluding oral and metastatic melanoma, Kaposi's sarcoma, myelomasincluding multiple myeloma, myeloproliferative disorders, proliferativediabetic retinopathy, or angiogenic-associated disorders including solidtumors;

Diabetes, including Type I diabetes or complications from diabetes;

Eye diseases, disorders or conditions including autoimmune diseases ofthe eye, keratoconjunctivitis, vernal conjunctivitis, uveitis includinguveitis associated with Behcet's disease and lens-induced uveitis,keratitis, herpetic keratitis, conical keratitis, corneal epithelialdystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis,Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome,keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis,sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis,allergic conjunctivitis, or ocular neovascularization;

Intestinal inflammations, including Crohn's disease, ulcerative colitis,inflammatory bowel disease, celiac diseases, proctitis, eosinophilicgastroenteritis, or mastocytosis;

Neurodegenerative diseases including motor neuron disease, Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, cerebral ischemia, or neurodegenerative diseasecaused by traumatic injury, strike, glutamate neurotoxicity or hypoxia;ischemic/reperfusion injury in stroke, myocardial ischemica, renalischemia, heart attacks, cardiac hypertrophy, atherosclerosis andarteriosclerosis, organ hypoxia, or platelet aggregation;

Skin diseases, conditions or disorders including atopic dermatitis,eczema, psoriasis, scleroderma, pruritus or other pruritic conditions,vitiligo, alopecia;

Allergic reactions including allergic dermatitis in mammal (includinghorse allergic diseases such as bite hypersensitivity), summer eczema,sweet itch in horses, heaves, inflammatory airway disease, recurrentairway obstruction, airway hyper-responsiveness, or chronic obstructionpulmonary disease;

Asthma and other obstructive airways diseases, including chronic orinveterate asthma, late asthma, bronchitis, bronchial asthma, allergicasthma, intrinsic asthma, extrinsic asthma, or dust asthma;

Transplant rejection, including pancreas islet transplant rejection,bone marrow transplant rejection, graft-versus-host disease, organ andcell transplant rejection such as bone marrow, cartilage, cornea, heart,intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast,nerve, pancreas, skin, small intestine, or trachea, or xenotransplantation.

Chemical Synthesis

The skilled person will appreciate that the experimental conditions setforth in the schemes that follow are illustrative of suitable conditionsfor effecting the transformations shown, and that it may be necessary ordesirable to vary the precise conditions employed for the preparation ofcompounds of formula (I). It will be further appreciated that it may benecessary or desirable to carry out the transformations in a differentorder from that described in the schemes, or to modify one or more ofthe transformations, to provide the desired compound of the invention.

All of the derivatives of formula (I) can be prepared by the proceduresdescribed in the general methods presented below or by routinemodifications thereof. The present invention also encompasses any one ormore of these processes for preparing the derivatives of formula (I), inaddition to any novel intermediates used therein. The person skilled inthe art will appreciate that the following reactions may be heatedthermally or under microwave irradiation.

It will be further appreciated that it may be necessary or desirable tocarry out the transformations in a different order from that describedin the schemes, or to modify one or more of the transformations, toprovide the desired compound of the invention.

The routes below, including those mentioned in the Examples andPreparations, illustrate methods of synthesising compounds of formula(I). The skilled person will appreciate that the compounds of theinvention, and intermediates thereto, could be made by methods otherthan those specifically described herein, for example by adaptation ofthe methods described herein, for example by methods known in the art.Suitable guides to synthesis, functional group interconversions, use ofprotecting groups, etc., are for example: “Comprehensive OrganicTransformations” by RC Larock, VCH Publishers Inc. (1989); AdvancedOrganic Chemistry” by J. March, Wiley lnterscience (1985); “DesigningOrganic Synthesis” by S Warren, Wiley lnterscience (1978); “OrganicSynthesis—The Disconnection Approach” by S Warren, Wiley lnterscience(1982); “Guidebook to Organic Synthesis” by R K Mackie and D M Smith,Longman (1982); “Protective Groups in Organic Synthesis” by TW Greeneand PGM Wuts, John Wiley and Sons, Inc. (1999); and “Protecting Groups”by P J, Kocienski, Georg Thieme Verlag (1994); and any updated versionsof said standard works.

In addition, the skilled person will appreciate that it may be necessaryor desirable at any stage in the synthesis of compounds of the inventionto protect one or more sensitive groups, so as to prevent undesirableside reactions. In particular, it may be necessary or desirable toprotect amino or carboxylic acid groups. The protecting groups used inthe preparation of the compounds of the invention may be used inconventional manner. See, for example, those described in ‘Greene'sProtective Groups in Organic Synthesis’ by Theodora W Greene and Peter GM Wuts, third edition, (John Wiley and Sons, 1999), in particularchapters 7 (“Protection for the Amino Group”) and 5 (“Protection for theCarboxyl Group”), incorporated herein by reference, which also describesmethods for the removal of such groups.

In the general synthetic methods below, unless otherwise specified, thesubstituents are as defined above with reference to the compounds offormula (I) above.

Where ratios of solvents are given, the ratios are by volume.

The compounds of the invention may be prepared by any method known inthe art for the preparation of compounds of analogous structure. Inparticular, the compounds of the invention can be prepared by theprocedures described by reference to the Schemes that follow, or by thespecific methods described in the Examples, or by similar processes toeither.

The skilled person will appreciate that the experimental conditions setforth in the schemes that follow are illustrative of suitable conditionsfor effecting the transformations shown, and that it may be necessary ordesirable to vary the precise conditions employed for the preparation ofcompounds of formula (I).

In addition, the skilled person will appreciate that it may be necessaryor desirable at any stage in the synthesis of compounds of the inventionto protect one or more sensitive groups, so as to prevent undesirableside reactions. In particular, it may be necessary or desirable toprotect amino or carboxylic acid groups. The protecting groups used inthe preparation of the compounds of the invention may be used inconventional manner. See, for example, those described in ‘Greene'sProtective Groups in Organic Synthesis’ by Theodora W Greene and Peter GM Wuts, third edition, (John Wiley and Sons, 1999), in particularchapters 7 (“Protection for the Amino Group”) and 5 (“Protection for theCarboxyl Group”), incorporated herein by reference, which also describesmethods for the removal of such groups.

All of the derivatives of formula (I) can be prepared by the proceduresdescribed in the general methods presented below or by routinemodifications thereof. The present invention also encompasses any one ormore of these processes for preparing the derivatives of formula (I), inaddition to any novel intermediates used therein. The person skilled inthe art will appreciate that the following reactions may be heatedthermally or under microwave irradiation.

It will be further appreciated that it may be necessary or desirable tocarry out the transformations in a different order from that describedin the schemes, or to modify one or more of the transformations, toprovide the desired compound of the invention. The schemes arerepresentative of methods useful in synthesizing the compounds of thepresent invention. They are not to constrain the scope of the inventionin any way.

According to a first process, compounds of formula I may be preparedfrom compounds of formulae (A), (B), (C) and (D), as illustrated byScheme 1.

In scheme 1, compound of the Formula Bi (where Y=Hal) is converted to acompound of Formula Bii (Y═B(OR*)₂) by treatment with a suitableboronate such as B₂(Pin)₂, in the presence of a suitable base, such asK₂CO₃, and a suitable catalyst, such as Pd(dppf)Cl₂ in a suitablesolvent, such as dioxane. A skilled person also knows that alternativeorganometallic coupling strategies can be used involving alternativecoupling partners, metals and solvent combinations. A compound of theFormula Bii is prepared and isolated as described above or prepared insitu without isolation in a sequential cross-coupling strategy that iswell understood by a skilled person. Thus, a compound of Formula Bii iscross-coupled with a compound of Formula A in the presence of a suitablecatalyst, such as Pd(dppf)Cl₂, with a suitable base, such as K₂CO₃ in asuitable solvent such as dioxane at a suitable temperature from roomtemperature to reflux temperature. The resulting compound of Formula Cis cross-coupled with a compound of the Formula D containing a suitableleaving group, such as Bu₃Sn or (Pin)₂B, with a suitable metal catalyst,such as Pd(PPh₃)₄, in a suitable solvent, such as MeCN at room orelevated temperatures.

According to a second process a compound of the Formula I is also beprepared by the organometallic cross-coupling reaction of compounds ofthe Formula F with compounds of Formula B, scheme 2.

Compound of the Formula Bi (where Y=Hal) is converted to a compound ofFormula Bii (Y═B(OR*)₂) by treatment with a suitable boronate such asB(Pin)₂, in the presence of a suitable base, such as K₂CO₃, and asuitable catalyst, such as Pd(dppf)Cl₂ in a suitable solvent, such asdioxane. A skilled person also knows that alternative organometalliccoupling strategies can be used involving alternative coupling partners,metals and solvent combinations. A compound of the Formula Bii isprepared and isolated as described above or prepared in situ withoutisolation in a sequential cross-coupling strategy that is wellunderstood by a skilled person. Thus, a compound of Formula Bii iscross-coupled with a compound of Formula F in the presence of a suitablecatalyst, such as Pd(dppf)Cl₂, with a suitable base, such as K₂CO₃ in asuitable solvent such as dioxane at a suitable temperature from roomtemperature to reflux temperature.

According to a third process, compound of Formula I is prepared by thealkylation, acylation, sulfonylation etc., of a compound of Formula G,Scheme 3.

According to a Fourth process, compound of Formula I is prepared by theMichael addition of a compound of Formula H with a compound of Formula Jin the presence of a suitable non-nucleophilic base, such as DBU in asuitable solvent, such as MeCN at a suitable temperature, scheme 4.

Scheme 5 illustrates a method for the preparation of compounds ofFormula F. A diester of Formula Ei is treated with an alkylating agentof Formula K and a base such as K₂CO₃ in a suitable solvent such asMeCN. The resulting diester of Formula Eii is then cyclized in thepresence NH₄OAc in a suitable solvent such as EtOH at elevatedtemperature to give bicyclic heterocyclic compound of Formula Eiii. Thecompound of Formula Eiii is hydrolysed to a compound of Formula Eiv witha suitable base, such as LiOH, in a suitable solvent such as MeOH. Theresulting carboxylic acid of Formula Eiv is thermally decarboxylated ina suitable solvent, such as sulfolane at elevated temperature such as280° C. The resulting compound of Formula Ev is chlorinated by treatmentwith a suitable reagent, such as POCl₃, in a suitable solvent, such asMeCN, at a suitable temperature such as reflux to prepare compounds ofthe Formula F.

The following schemes and written descriptions provide general detailsregarding the preparation of the compounds of the invention. Thecompounds of the invention may be prepared by any method known in theart for the preparation of compounds of analogous structure. Inparticular, the compounds of the invention can be prepared by theprocedures described by reference to the schemes that follow, or by thespecific methods described in the examples, or by similar processes toeither.

The skilled person will appreciate that the experimental conditions setforth in the schemes that follow are illustrative of suitable conditionsfor effecting the transformations shown, and that it may be necessary ordesirable to vary the precise conditions employed for the preparation ofcompounds of formula (I).

In addition, the skilled person will appreciate that it may be necessaryor desirable at any stage in the synthesis of compounds of the inventionto protect one or more sensitive groups, so as to prevent undesirableside reactions. In particular, it may be necessary or desirable toprotect amino or carboxylic acid groups. The protecting groups used inthe preparation of the compounds of the invention may be used inconventional manner. See, for example, those described in ProtectiveGroups in Organic Synthesis by Theodora W. Greene and Peter G. M. Wuts,3rd edition, (John Wiley and Sons, 1999), in particular chapters 7(“Protection for the Amino Group”) and 5 (“Protection for the CarboxylGroup”), incorporated herein by reference, which also describes methodsfor the removal of such groups.

All of the derivatives of formula I and Ia-f can be prepared by theprocedures described in the general methods presented below or byroutine modifications thereof. The present invention also encompassesany one or more of these processes for preparing the derivatives offormula (I), in addition to any novel intermediates used therein. Theperson skilled in the art will appreciate that the following reactionsmay be heated thermally or under microwave irradiation.

In executing the synthesis of the compounds of the invention, oneskilled in the art will recognize the need to sample and assay reactionmixtures prior to work up in order to monitor the progress of reactionsand decide whether the reaction should be continued or whether it isready to be worked up to obtain the desired product. Common methods forassaying reaction mixtures include thin-layer chromatography (TLC),liquid chromatography/mass spectroscopy (LCMS), and nuclear magneticresonance (NMR).

One skilled in the art will also recognize that the compounds of theinvention may be prepared as mixtures of diastereomers or geometricisomers (e.g., cis and trans substitution on a cycloalkane ring). Theseisomers can be separated by standard chromatographic techniques, such asnormal phase chromatography on silica gel, reverse phase preparativehigh pressure liquid chromatography or supercritical fluidchromatography. One skilled in the art will also recognize that somecompounds of the invention are chiral and thus may be prepared asracemic or scalemic mixtures of enantiomers. Several methods areavailable and are well known to those skilled in the art for theseparation of enantiomers. A preferred method for the routine separationenantiomers is supercritical fluid chromatography employing a chiralstationary phase.

Experimental Section

Except where otherwise noted, reactions were run under an atmosphere ofnitrogen.

Chromatography on silica gel was carried out using 250-400 mesh silicagel using pressurized nitrogen (˜10-15 psi) to drive solvent through thecolumn (“flash chromatography”). Where indicated, solutions and reactionmixtures were concentrated by rotary evaporation under vacuum.

The nomenclature in this patent is written as described by IUPAC(International Union of Pure and Applied Chemistry and using ChemBioDrawUltra 13.0, Perkin Elmer to generate names.

The following non-limiting Preparations and Examples illustrate thepreparation of compounds and salts of the present invention. In theExamples and Preparations that are set out below, and in theaforementioned Schemes, the following abbreviations, definitions andanalytical procedures may be referred to. Other abbreviations common inthe art may also be used. Standard IUPAC nomenclature has been used.

AcOH is acetic acid;aq. is aqueous;Boc is tert-butoxycarbonyl;br is broad;brine is a saturated solution of sodium chloride in water;t-Bu is tert-butyl;n-BuLi is n-butyllithium;° C. is degrees celcius;Cbz is carbobenzyloxy;CDCl₃ is deutero-chloroform;CDI is 1,1′-carbonyldiimidazole;conc. is concentrated (in reference to reagents);Cs₂CO₃ is cesium carbonate;δ is chemical shift;d is doublet;DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene;DCM is dichloromethane;DHP is 3,4-dihydro-2H-pyran;

DIPEA is N,N-diisopropylethylamine;

DMAP is 4-dimethylaminopyridine;

DMF is N,N-dimethylformamide;

DMSO is dimethyl sulfoxide;Et₂O is diethyl ether;EtOAc is ethyl acetate;EtOH is ethanol;(EtO)₂P(O)CH2CN is diethyl (cyanomethyl)phosphonate;g is gram;GCMS is gas chromatography mass spectrometryHCl is hydrochloric acid;HCO₂H is formic acid;HPLC is high performance liquid chromatography;hrs is hours;H₂SO₄ is sulfuric acid;K₂CO₃ is potassium carbonate;KH₂PO₄ is potassium dihydrogen phosphateK₂HPO₄ is potassium monohydrogen phosphate;K₃PO₄ is potassium phosphate (tribasic);KOAc is potassium acetateL is liter;LCMS is liquid chromatography mass spectrometry;LiBr is lithium bromide;LiOH is lithium hydroxide;m is multiplet;M is molar;MeCN is acetonitrile;MeOH is methanol;mg is milligram;MgSO₄ is magnesium sulfate;MHz is megaHertz;min is minutes;mL is milliliter;mmol is millimole;mol is mole;MS m/z is mass spectrum ion peak;MTBE is methyl t-butyl etherNaBH(OAc)₃ is sodium triacetoxyborohydride;Na₂CO₃ is sodium carbonate;NaHCO₃ is sodium hydrogen carbonate;NaH₂PO₄ is sodium dihydrogen phosphate;Na₂HPO₄ is sodium monohydrogen phosphate;NaI is sodium iodide;NaIO₄ is sodium periodate;NaOAc is sodium acetate;NaOCl is sodium hypochlorite;NaOH is sodium hydroxide;NH₃ is ammonia;NH₄Cl is ammonium chloride;NH₄OH is ammonium hydroxide;NH₄OAc is ammonium acetate;NMR is nuclear magnetic resonance;OsO₄ is osmium tetroxide;Pd/C is palladium on carbon;Pd(dppf)Cl₂ is 1,1-bis(diphenylphosphino)ferrocenepalladium(II)dichloride (CAS: 72287-26-4);

Pd(dppf)Cl₂ DCM is 1,1-bis(diphenylphosphino)ferrocenepalladium(II)dichloride; complex with dichloromethane (CAS: 95464-05-4);

Pd(OAc)₂ is palladium acetate;Pd(PPh₃)₄ is tetrakis(triphenylphosphine)palladium;PMB-Cl is (4-methoxy)benzyl chloride;POCl₃ is phosphorus(V) oxychloride;ppm is parts per million;psi is pounds per square inch;PTSA is para-toluenesulfonic acidPyHBr₃ is pyridine hydrobromide perbromidePyHCl is pyridine hydrochlorideq is quartet;Rt is retention time;Rh₂(OAc)₄ is rhodium (II) acetate dimer;RuCl₃ hydrate is ruthenium(II) chloride hydrate;s is singlet;SOCl₂ is thionyl chloride;t is triplet;TBAB is tetrabutylammonium bromideTEA is triethylamine;TFA is trifluoroacetic acid;THF is tetrahydrofuran;TMSCl is chorotrimethylsilane;μL is microliter;μmol is micromoleXPhos Pd G2 ischloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II);CAS 1310584-14-5.

¹H Nuclear magnetic resonance (NMR) spectra were in all cases consistentwith the proposed structures. Characteristic chemical shifts (δ) aregiven in parts-per-million downfield from tetramethylsilane usingconventional abbreviations for designation of major peaks: e.g. s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.The following abbreviations have been used for common NMR solvents:CD₃CN, deuteroacetonitrile; CDCl₃, deuterochloroform; DMSO-d₆,deuterodimethylsulfoxide; and CD₃OD, deuteromethanol. Where appropriate,tautomers may be recorded within the NMR data; and some exchangeableprotons may not be visible.

Mass spectra were recorded using electron impact ionization (EI),electrospray ionisation (ESI) or atmospheric pressure chemicalionisation (APCl). The observed ions are reported as MS m/z and may bepositive ions of the compound [M]⁺, compound plus a proton [MH]⁺, orcompound plus a sodium ion [MNa]⁺. In some cases the only observed ionsmay be fragment ions reported as [MH-(fragment lost)]⁺. Where relevant,the reported ions are assigned for isotopes of chlorine (Cl³⁵ and/or³⁷Cl), bromine (⁷⁹Br and/or ⁸¹Br) and tin (¹²⁰Sn).

Wherein TLC, chromatography, or HPLC has been used to purify compounds,one skilled in the art may choose any appropriate solvent or combinationof solvents to purify the desired compound. Chromatographic separations(excluding HPLC) were carried out using silica gel adsorbent unlessotherwise noted.

All reactions were carried out using continuous stirring under anatmosphere of nitrogen or argon gas unless otherwise noted. In somecases, reactions were purged with nitrogen or argon gas prior to thestart of the reaction. In these cases, the nitrogen or argon gas wasbubbled through the liquid phase of the mixture for the approximatespecified time. Solvents used were commercial anhydrous grades. Allstarting materials were commercially available products. In some cases,the Chemical Abstracts Service (CAS) identification number is providedto assist with clarity. In some cases, starting materials were preparedaccording to reported literature procedures as indicated by an asterisk(*). It will be apparent to one skilled in the art that the word“concentrated” as used herein generally refers to the practice ofevaporation of solvent under reduced pressure, typically accomplished bythe use of a rotary evaporator.

GCMS Conditions

Column: 12 m×0.2 mm, HP-1 Methyl Siloxane, 0.33 μm film, 1.0 ml/mincolumn flow.Methods: 7.6 min: Initial Oven Temp 105° C.; 0.1 min hold; 30° C./minramp to 300° C. endpoint at 7.6 min; or 7.6 min: Initial Oven Temp 60°C.; 0.1 min hold; 40° C./min ramp to 320° C. endpoint at 7.6 min; or 5.1min: Initial Oven Temp 40° C.; 0.1 min hold; 30° C./min ramp to 150° C.endpoint at 5.1 min.GC Inlet Parameters: Front Inlet, Split 30:1, He, 8 psi pressure, 250°C. Injector, 33.9 ml/min total flow.

MSD Tune: 230° C. Source Temp, 150° C. Quad Temp, 280° C. Aux2 TempInjection Volume: 1.0 μL

System Components: Agilent 5890 GC Oven with Agilent 5973 Mass SelectiveDetector

LCMS Conditions

Acid: Waters Acquity HSS T3, 2.1 mm×50 mm, C18, 1.7 μm; ColumnTemperature 60° C.Base: Waters Acquity UPLC BEH, 2.1 mm×50 mm, C18, 1.8 μm; ColumnTemperature 60° C.Mobile Phase: A: 0.1% formic acid in water (v/v); Mobile phase B: 0.1%formic acid in acetonitrile (v/v).Mobile Phase A: 0.1% ammonia in water (v/v); Mobile phase B: 0.1%ammonia in acetonitrile (v/v)Gradient Profiles: 1.5 min Run: Initial conditions: A-95%:B-5%; hold atinitial from 0.0-0.1 min; Linear Ramp to A-5%:B-95% over 0.1-1.0 min;hold at A-5%:B-95% from 1.0-1.1 min; return to initial conditions1.1-1.5 min

Purification Methods (PM)

The compounds of the Examples were purified according to one of thePurification Methods (PM) referred to below unless otherwise described:

Purification Method A: Preparative HPLC using [Agella venusil ASB C18150×21.2 mm×5 μm, from 16% MeCN in water (0.225% formic acid) to 36%MeCN in water (0.225% formic acid)]Purification Method B: Preparative HPLC using [Phenomenex Gemini C18250×21.2 mm×8 um or 150 mm×25 mm×5 μm; from 16-55% MeCN in water (0.1%ammonia) to 36-60% MeCN in water (0.1% ammonia)]Purification Method C: [YMC-Actus Triart C18 150×30 μm, from 24% MeCN inwater (0.1% ammonia) to 44% MeCN in water (0.1% ammonia)]Purification Method D: Preparative HPLC using [Phenomenex Gemini C18250×21.2 mm×8 μm, from 25% MeCN in water (ammonia pH=10) to 45% MeCN inwater (ammonia pH=10)] followed by chiral chromatography using AS 250×25mm I.D. 20 μM column, with supercritical CO₂: EtOH or IPA (0.05% aqueousammonia) 70:30 at from 50-80 mL/minPurification Method E: Preparative HPLC using [Phenomenex Gemini C18250×21.2 mm×8 μm, from 25% MeCN in water (0.225% ammonia) to 45% MeCN inwater (0.225% ammonia) followed by chiral chromatography using AD 250mm×30 mm×20 μm column with mobile phase A: supercritical CO₂ and mobilephase B MeOH with 0.1% ammonia A:B 50:50 at 180 mL/minPurification Method F: Silica gel column chromatography eluting with100% DCM to 12% MeOH with 1% NH₄OH.Purification Method G: Silica gel column chromatography eluting with97:2:1 DCM:MeOH:NH₃ followed by preparative HPLC.Purification Method H: Preparative HPLC using Column: Waters XBridge C1819 mm×100 mm, 5μ; Mobile phase A: 0.03% ammonium hydroxide in water(v/v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v);from 5-20% B to 40-100% B at 25 mL/min flow rate.Purification Method I: Preparative HPLC using Column: Waters Sunfire C1819 mm×100 mm, 5μ; Mobile phase A: 0.05% TFA in water (v/v); Mobile phaseB: 0.05% TFA in acetonitrile (v/v); from 20% B to 40% B at 6.75 minutes,then to 100% B at 7 minutes at 30 mL/min flow rate.

Specific Rotation

Specific rotations based on the equation [α]=(100·α)/(I·c) and arereported as unitless numbers where the concentration c is in g/100 mLand the path length l is in decimeters. The units of the specificrotation, (deg·mL)/(g·dm), are implicit and are not included with thereported value.

Preparation 1 Ethyl 1-(cyanomethyl)-1H-pyrazole-3-carboxylate

and

Ethyl 1-(cyanomethyl)-1H-pyrazole-5-carboxylate

To a suspension of Cs₂CO₃ (2100 g, 6.44 mol) in DMF (12 L) was addedethyl 1H-pyrazole-3-carboxylate (750 g, 5.36 mol), followed by2-chloroacetonitrile (450 g, 5.96 mol) and the mixture was stirred atabout 25° C. for about 16 hrs. The reaction was poured into water (12 L)and extracted with EtOAc (5×5 L). The combined EtOAc extracts werewashed with brine (2×5 L), dried (Na₂SO₄) and concentrated to afford aresidue which was purified by chromatography to afford ethyl1-(cyanomethyl)-1H-pyrazole-3-carboxylate (398 g, 39%) as a yellow oiland ethyl 1-(cyanomethyl)-1H-pyrazole-5-carboxylate (680 g). The ethyl1-(cyanomethyl)-1H-pyrazole-5-carboxylate was dissolved in MTBE (15 L)and washed with brine (3×5 L), dried (Na₂SO₄) and concentrated to affordthe compound as a yellow oil (489 g, 51%).

¹H NMR (400 MHz, CDCl₃) δ: 7.49 (s, 1H), 6.82 (s, 1H), 5.45 (s, 2H),4.29 (q, 2H), 1.29 (t, 3H)

LCMS m/z=180.1 [MH]⁺

Preparation 2 Ethyl 1-(2-amino-2-oxoethyl)-1H-pyrazole-5-carboxylate

Two identical reactions were carried out in parallel.

To a solution of ethyl 1-(cyanomethyl)-1H-pyrazole-5-carboxylate(Preparation 1, 235.5 g, 1.32 mol) in TFA (1.2 L) was added conc. H₂SO₄(377 mL, 7.04 mol) at about 25° C. The reaction mixture was stirred atabout 25° C. for about 16 hrs before being combined with the parallelreaction and concentrated to remove most of the TFA. The residue waspoured into ice-water (5 L) and extracted with EtOAc (5 L). The aqueousphase was further extracted with EtOAc (10×5 L) and the combined EtOAcextracts were washed with saturated aq. NaHCO₃ (2×10 L), dried (Na₂SO₄)and concentrated to afford the title compound as a yellow solid (477 g,92%).

¹H NMR (400 MHz, CDCl₃) δ: 7.60 (s, 1H), 6.93 (s, 1H), 5.90 (br. s, 1H),5.71 (br. s, 1H), 5.27 (s, 2H), 4.35 (q, 2H), 1.37 (t, 3H).

LCMS m/z=198.2 [MH]⁺

Preparation 3 Pyrazolo[1,5-a]pyrazine-4,6(5H,7H)-dione

To a solution of ethyl 1-(2-amino-2-oxoethyl)-1H-pyrazole-5-carboxylate(Preparation 2, 466 g, 2.17 mol) in EtOH (56 L) was added NaOtBu (498 g,5.20 mol) in THF (4 L) at about 25° C. A white suspension developedduring the addition and the mixture was then heated to about 70° C. forabout 16 hrs. The reaction mixture was cooled to about 25° C. andacidified to about pH 6 with 12 M aq. HCl (500 mL), resulting in theformation of a white suspension. The mixture was concentrated to affordthe title compound (admixed with sodium chloride) as yellow solid (783g). This was used without further purification.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.82 (s, 1H), 7.74 (s, 1H), 6.97 (s, 1H),5.19 (s, 2H). LCMS m/z=152.1 [MH]⁺

Preparation 4 4,6-Dichloropyrazolo[1,5-a]pyrazine

Three identical reactions were carried out in parallel.

Pyrazolo[1,5-a]pyrazine-4,6(5H,7H)-dione (Preparation 3, 278 g, 1.14mol) was added to POCl₃ (1.84 kg, 12 mol) at about 25° C., followed byPyHCl (131 g, 1.14 mol). The reaction mixture was heated at about 120°C. for about 16 hrs. The reactions were cooled to about 25° C. andconcentrated to remove most of the POCl₃. Each residue was diluted withEtOAc (2 L) and the three EtOAc extracts were combined and poured into 1M aq. NaH₂PO₄ (7.5 L) at about 25° C. and filtered through a pad ofCelite®. The filter cake was washed with EtOAc (3×2 L) and all filtrateswere combined and separated from the aqueous phase. The aqueous phasewas extracted with MTBE (10 L). The combined EtOAc and MTBE extractswere washed with brine (2×5 L), dried (Na₂SO₄) and concentrated. Theresidue was purified by chromatography and the product was trituratedwith petroleum ether (300 mL) and filtered. The filter cake was dried toafford the title compound as a white solid (110 g, 22%).

¹H NMR (400 MHz, CDCl₃) δ: 8.42 (s, 1H), 8.06 (s, 1H), 6.93 (s, 1H).

LCMS m/z=189.8 [MH]⁺ (Cl³⁷ isotope)

Preparation 5 1-(1-Methyl-1H-pyrazol-4-yl)ethan-1-one

Two identical reactions were carried out in parallel.

To a mixture of 1-methylpyrazole (750 g, 9.16 mol) and acetic anhydride(1.7 kg, 16.67 mol) was added concentrated H₂SO₄ (75 g, 0.75 mol) atabout 20° C. The reaction mixture was heated at about 150° C. for about3 hrs. After cooling, the two mixtures were combined, poured intoice-water (15 L), adjusted to about pH 10 with 20% aq. NaOH andextracted with DCM (4×10 L). The combined DCM extracts were dried(Na₂SO₄) and concentrated to afford the title compound as a brown oil(1240 g, 72%).

¹H NMR (400 MHz, CDCl₃) δ: 7.86 (s, 1H), 7.84 (s, 1H), 3.92 (s, 3H),2.40 (s, 3H).

GCMS m/z=109.0 [M−CH₃]⁺

Preparation 6 2-Bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one

Two identical reactions were carried out in parallel.

To a solution of 1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one (Preparation 5,620 g, 5 mol) in DCM (12 L) and ethanol (3 L) was added PyHBr₃ (1.6 kg,5 mol) at about 15° C. The mixture was stirred at about 15° C. for about18 hrs. The two reaction mixtures were combined, quenched with water (10L), separated, and the aqueous phase was extracted with DCM (4×10 L).The combined DCM extracts were dried (Na₂SO₄) and concentrated to removeabout 69 L of solvent. The residue was diluted with petroleum ether (5L), stirred at about 15° C. for about 30 min and the mixture wasfiltered. The precipitate was dried to afford the title compound as ayellow solid (1.73 kg, 85%).

¹H NMR (400 MHz, CDCl₃) δ: 7.97 (s, 1H), 7.91 (s, 1H), 4.17 (s, 2H),3.93 (s, 3H).

LCMS m/z=203.1 [MH]⁺ (⁷⁹Br isotope)

Preparation 7 Diethyl1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate

Two reactions were carried out in parallel.

To a mixture of 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one(Preparation 6; 500 g, 2.46 mol) anddiethyl-1H-pyrazole-3,5-dicarboxylate (580 g, 2.73 mol) in DMF (8 L) wasadded Cs₂CO₃ (1050 g, 3.23 mol) at about 20° C. After about 18 hrs, thetwo reaction mixtures were combined, diluted with water (10 L) andextracted with DCM (3×10 L). The combined DCM extracts were dried(Na₂SO₄) and concentrated. The residue was purified by chromatography toafford the title compound as a yellow solid (1.53 kg, 93%).

¹H NMR (400 MHz, CDCl₃) δ: 7.96 (s, 2H), 7.46 (s, 1H), 5.86 (s, 2H),4.45 (q, 2H), 4.32 (q, 2H), 3.99 (s, 3H), 1.44 (t, 3H), 1.36 (t, 3H).

LCMS m/z=335.0 [MH]⁺

Preparation 8 Ethyl4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate

Three identical reactions were carried out in parallel.

To a solution of diethyl1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate(Preparation 7; 510 g, 1.52 mol) in ethanol (6 L) was added NH₄OAc (352g, 4.57 mol) at about 20° C. The mixture was heated in an autoclave atabout 130° C. for about 24 hrs. The reaction mixtures were cooled toabout 50° C. and were combined and filtered. The precipitate was driedto afford the title compound (1090 g, 83%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.35 (br. s, 1H), 8.31 (s, 1H), 8.20 (s,1H), 8.05 (s, 1H), 7.38 (s, 1H), 4.34 (q, 2H), 3.89 (s, 3H), 1.33 (t,3H).

LCMS m/z=288.0 [MH]⁺

Preparation 94-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylicacid

Two identical reactions were carried out in parallel.

To a suspension of ethyl4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate(Preparation 8, 545 g, 1.9 mol) in MeOH (10 L) was added 1 M aq. NaOH(5.75 L) at about 20° C. After about 30 min, the suspension became aclear solution and stirring was continued at about 20° C. for about 18hrs. The reaction mixtures were adjusted to about pH 2 with 12 M aq. HCl(650 mL), combined, and concentrated to remove most of the MeOH. Theresidue was filtered and the precipitate was dried to afford the titlecompound as an off-white solid (1040 g, 100%).

¹H NMR (400 MHz, DMSO-d₆) δ: 13.25 (br. s, 1H), 11.67 (s, 1H), 8.34 (s,1H), 8.16 (s, 1H), 8.06 (s, 1H), 7.32 (s, 1H), 3.88 (s, 3H).

LCMS m/z=260.0 [MH]⁺

Preparation 10 6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol

Five identical reactions were carried out in parallel.

4-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylicacid (Preparation 9, 85 g, 0.328 mol) was added in portions topre-heated sulfolane (800 mL) at about 280° C. The five reactionmixtures were stirred at about 280° C. for about 2 hrs, cooled to about25° C., and stirred for about 18 hrs. The reaction mixtures werecombined and the mixture was purified by chromatography eluting withpetroleum ether-EtOAc (10:1 to 0:1), followed by DCM-MeOH (10:1) toafford the title compound as a yellow solid (490 g, 75%).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.45 (s, 1H), 8.28 (s, 1H), 8.10 (s, 1H),8.04 (s, 1H), 7.88 (5, 1 H), 6.99 (s, 1H), 3.88 (s, 3H).

LCMS m/z=216.0 [MH]⁺

Preparation 114-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

Two identical reactions were carried out in parallel.

To a suspension of6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol (Preparation 10,307 g, 1.43 mol) in MeCN (7.5 L) was added POCl₃ (2006 g, 13 mol) atabout 25° C. The mixture was heated at about 85° C. for about 48 hrs.The reaction mixtures were combined and filtered. The precipitate waswashed with EtOAc and dried under vacuum. The dried precipitate waspurified by chromatography to afford a yellow solid which was dissolvedin DCM (15 L) and washed with 1 M aq. NaHCO₃ (5 L). The DCM concentratedto remove about 13 L of solvent and the residue was diluted MTBE (2 L)and petroleum ether (2 L). The mixture was filtered and the precipitatewas dried to afford the title compound as a yellow solid (385 g, 58%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.22 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H),8.04 (s, 1H), 7.02 (s, 1H), 3.88 (s, 3H).

LCMS m/z=233.8 [MH]⁺ (Cl³⁵ isotope)

Preparation 12 1-(4-Methoxybenzyl)-1H-pyrazole-4-carboxylic acid

Part 1: Three identical reactions were carried out in parallel.

To a stirred solution of ethyl 1H-pyrazole-4-carboxylate (16 g, 110mmol) in MeCN (160 mL) was added PMB-CI (85.8 g, 548 mmol) and K₂CO₃(23.7 g, 171 mmol) and the mixture was heated under reflux for about 18hrs. The three batches were cooled, combined and filtered. The filtratewas concentrated to afford ethyl1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate as a yellow oil that wasused without further purification.

Part 2: Three identical reactions were carried out in parallel.

To a stirred solution of crude ethyl1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (Part 1, 50.0 g, 96 mmol)in THF (150 mL) and MeOH (150 mL) was added a solution of LiOH (10 g,238 mmol) in water (75 mL). The mixture was heated at about 60° C. forabout 18 hrs. The three batches were combined and evaporated to dryness.The residue was diluted with water (800 mL) and MeOH (150 mL) and washedwith EtOAc (2×500 mL). The EtOAc extracts were discarded and the aqueoussolution was acidified to about pH 2 with 6 M aq. HCl and extracted withEtOAc (2×800 mL). The combined EtOAc extracts were washed with brine(500 mL), dried (Na₂SO₄) and concentrated to afford the title compoundas a white solid (33.0 g, 83% for the two steps).

¹H NMR (400 MHz, DMSO-d₆) δ: 12.34 (br. s, 1H), 8.32 (s, 1H), 7.79 (s,1H), 7.23 (m, 2H), 6.89 (m, 2H), 5.26 (s, 2H), 3.72 (s, 3H).

Preparation 13 1-(4-Methoxybenzyl)-1H-pyrazole-4-carbonyl chloride

A solution of 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid(Preparation 12, 25.0 g, 110 mmol) in SOCl₂ (40 mL) was stirred at about60° C. for about 5 hrs. The solution was concentrated to afford titlecompound as a brown oil (27.0 g, 100%) which was used without furtherpurification or characterization.

Preparation 14N-Methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide

To a solution of N,O-dimethylhydroxylamine hydrochloride (26.3 g, 269mmol) and TEA (131.0 g, 1.29 mol) in DCM (200 mL) was slowly added asolution of 1-(4-methoxybenzyl)-1H-pyrazole-4-carbonyl chloride(Preparation 13, 27.0 g, 108 mmol) in DCM (50 mL). After the additionwas complete, the reaction mixture was stirred at about 20° C. for about5 hrs. The mixture was diluted with DCM (150 mL) and water (300 mL). Thecombined DCM extracts were washed with brine, dried (Na₂SO₄) andconcentrated to afford the title compound (20.0 g, 67%) as a brown oilwhich was used without further purification.

¹H NMR (400 MHz, CDCl₃) δ: 7.99 (s, 1H), 7.90 (s, 1H), 7.22 (d, 2H),6.89 (d, 2H), 5.25 (s, 2H), 3.81 (s, 3H), 3.69 (s, 3H), 3.31 (s, 3H).

LCMS m/z=275.0 [MH]⁺

Preparation 15 1-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)ethan-1-one

Two identical reactions were carried out in parallel.

To a solution of N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide(Preparation 14, 10.0 g, 36.3 mmol) in THF (120 mL) was added dropwise 3M methylmagnesium bromide in ether (24.2 mL) at about 0° C. The reactionmixture was warmed to about 25° C. and stirred for about 5 hrs. Thereaction was quenched by the addition of saturated aq. NH₄Cl (100 mL)and extracted with EtOAc (2×200 mL). The combined EtOAc extracts weredried (Na₂SO₄) and concentrated. The concentrated residues from bothexperiments were combined and purified by chromatography to afford thetitle compound (10.0 g, 60%) as a brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ: 8.47 (s, 1H), 7.91 (s, 1H), 7.25 (m, 2H),6.90 (m, 2H), 5.27 (s, 2H), 3.72 (s, 3H), 2.34 (s, 3H).

LCMS m/z=231.7 [MH]⁺

Preparation 162-Bromo-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)ethan-1-one

Two identical reactions were carried out in parallel.

To a solution of 1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)ethan-1-one(Preparation 15, 8.0 g, 34.7 mmol) in DCM (96 mL) and EtOH (24 mL) wasadded PyHBr₃ (13.3 g, 41.7 mmol) at about 20° C. The reaction mixtureswere kept at about 25° C. for about 18 hrs and quenched with water (100mL) before being combined and extracted with EtOAc (2×300 mL). Thecombined EtOAc extracts were washed with brine, dried (Na₂SO₄) andconcentrated. The residue was purified by chromatography to afford ayellow solid. This was triturated with MTBE (100 mL) to afford the titlecompound (15.0 g, 70%) as a yellow solid. An additional sample (5.0 g,23%) of slightly impure product was obtained as a yellow solid byconcentration of the trituration liquors.

¹H NMR (400 MHz, CDCl₃) δ: 7.99 (s, 1H), 7.89 (s, 1H), 7.23 (m, 2H),6.92 (m, 2H), 6.92 (m, 2H), 5.25 (s, 2H), 4.15 (s, 2H), 3.81 (s, 3H).

LCMS m/z=333.0 [MNa]⁺ (⁸¹Br isotope)

Preparation 17 Dimethyl1-(2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate

To a mixture of dimethyl 1H-pyrazole-3,5-dicarboxylate (1 g, 5 mmol) and2-bromo-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)ethan-1-one (Preparation16, 2.18 g, 7.06 mmol) in DMF (20 mL) was added Cs₂CO₃ (2.3 g, 7.06mmol) at about 20° C. After about 2 days, the mixture was concentratedto dryness. The residue was dissolved in DCM and washed once withsaturated aq. NH₄Cl. The DCM was concentrated and the residue waspurified by chromatography. The product was stirred in EtOAc (20 mL) atabout 20° C. for about 18 hrs. The solid formed was filtered and driedto afford the title compound (1.38 g, 60%).

¹H NMR (400 MHz, CDCl₃) δ: 7.96 (s, 1H), 7.82 (s, 1H), 7.42 (s, 1H),7.24 (d, 2H), 6.93 (d, 2H), 5.80 (s, 2H), 5.27 (s, 2H), 3.95 (s, 3H),3.84 (s, 3H), 3.83 (s, 3H).

LCMS m/z=413.1 [MH]⁺

Preparation 18 Methyl4-hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate

and

Ethyl4-hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate

Six identical reactions were carried out in parallel.

To each of six vials was added dimethyl1-(2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate(Preparation 17, 300 mg, 0.73 mmol), NH₄OAc (336 mg, 4.37 mmol) and EtOH(6 mL). The mixtures were heated under microwave irradiation at about150° C. for about 2 hrs, then cooled to about 20° C., stirred for about1 hrs, and filtered. The combined solids were dried to afford a mixtureof both title compounds which was used without further purification inthe next step (1.61 g).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.65 (br. s., 1H), 8.38 (s, 1H), 8.17 (s,1H), 8.07 (s, 1H), 7.36 (s, 1H), 7.26 (d, 2H), 6.93 (d, 2H), 5.75 (s,1H), 5.28 (s, 2H), 3.86 (s, 3H), 3.74 (s, 3H). This is the methyl esterwhich was the major component.

LCMS m/z=380.1 [MH]⁺, 394.1 [MH]⁺

Preparation 194-Hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylicacid

To a solution of the mixture of methyl4-hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylateand ethyl4-hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate(Preparation 18, 524 mg, about 1.38 mmol) in MeOH (10 mL) was added 1 Maq. NaOH (4.83 mL). The mixture was kept at about 20° C. for about 18hrs before additional 1 M aq. NaOH (1.38 mL) was added. The mixture waskept at about 20° C. for about 24 additional hours. The MeOH wasevaporated and the residue was diluted with water (2 mL) and stirred atabout 40° C. until all solid was dissolved. The solution was acidifiedwith 12 M aq. HCl and stirred at about 0° C. for about 10 min. Theresulting precipitate was filtered and the precipitate was washed withwater. The solid was dried under vacuum to afford the title compound(487 mg, 96%).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.65 (s, 1H), 8.38 (s, 1H), 8.18 (m, 1H),8.10 (s, 1H), 7.25-7.32 (m, 4H), 6.95 (m, 2H), 5.28 (s, 2H), 3.78 (s,3H).

LCMS m/z=366.0 [MH]⁺

Preparation 206-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)42yrazole[1,5-a]42yrazole-4-ol

Three reactions were carried out in parallel.

Sample 1:4-Hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)42yrazole[1,5-a]pyrazine-2-carboxylicacid

(Preparation 19, 40 mg, 0.11 mmol) was heated at about 350° C. for about10 seconds until the off white solid melted and turned into dark brownliquid.

Sample 2:4-hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)42yrazole[1,5-a]pyrazine-2-carboxylicacid

(Preparation 19, 120 mg, 0.33 mmol) was heated at about 350° C. forabout 15 seconds until the off white solid melted and turned into darkbrown liquid.

Sample 3:4-hydroxy-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)42yrazole[1,5-a]pyrazine-2-carboxylicacid

(Preparation 19, 310 mg, 0.85 mmol) was heated at about 350° C. forabout 15 seconds until the off white solid all melted and turned intodark brown liquid.

All three batches were cooled, combined and concentrated twice withtoluene to afford the title compound which was used without additionalpurification in the next step.

¹H NMR (400 MHz, DMSO-d₆) δ: 11.43 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H),8.08 (s, 1H), 7.88 (d, 1H), 7.28 (d, 2H), 6.99 (d, 1H), 6.94 (d, 2H),5.28 (s, 2H), 3.76 (s, 3H).

LCMS m/z=322.1 [MH]⁺

Preparation 214-Chloro-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

6-(1-(4-Methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol(Preparation 20, 390 mg, 1.21 mmol), PyHCl (143 mg, 1.21 mmol) and POCl₃(10 mL) were heated at about 120° C. for about 18 hrs. The mixture wasconcentrated and the residue was treated with aq. NaH₂PO₄ solution tomaintain about pH 4. The resulting solution was stirred at about 20° C.for about 10 min and extracted three times with DCM. The combined DCMextracts were dried and concentrated to afford the title compound as abrown solid (300 mg, 72%).

¹H NMR (400 MHz, CDCl₃) δ: 8.74 (s, 1H), 8.50 (s, 1H), 8.22 (m, 2H),7.45 (m, 2H), 6.92-7.02 (m, 3H), 3.88 (s, 2H), 2.15 (s, 3H).

LCMS m/z=340.0 [MH]⁺

Preparation 22 tert-Butyl4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazole-1-carboxylate

A solution of 4,6-dichloropyrazolo[1,5-a]pyrazine (Preparation 4, 700mg, 3.72 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(1100 mg, 3.72 mmol), 2 M aq. K₃PO₄ (3 mL, 6 mmol) in 1,4-dioxane (10.0mL) was purged with argon for about 5 min. To this was addedbis(tri-t-butylphosphine)palladium(0) (96.1 mg, 0.19 mmol) and thereaction was kept at about 20° C. for about 18 hrs. The solvent wasconcentrated to afford an amber residue which was taken up in DCM andpurified by chromatography to afford the title compound (710 mg, 60%).

¹H NMR (400 MHz, CDCl₃) δ: 8.82 (m, 1H), 8.44 (m, 3H), 8.14 (s, 1H),1.60 (s, 9H).

LCMS m/z=220.1 [MH-BOC]⁺

Preparation 23 tert-Butyl4-(6-vinylpyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazole-1-carboxylate

A solution of tert-butyl4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazole-1-carboxylate(Preparation 22, 700 mg, 2.19 mmol) and tributyl(vinyl)stannane (694 mg,2.19 mmol) in 1,4-dioxane (30 mL) was purged with argon for about 5 minfollowed by the addition of XPhos Pd G2 (344 mg, 0.44 mmol). The mixturewas heated to about 55° C. for about 18 hrs. The mixture wasconcentrated and the residue was purified by chromatography to affordthe title compound (449 mg, 66%).

¹H NMR (400 MHz, CDCl₃) δ: 8.79 (s, 1H), 8.46 (s, 1H), 8.26 (s, 1H),8.07 (d, 1H), 6.95 (dd, 1H), 6.77 (dd, 1H), 6.43 (dd, 1H), 5.52 (dd,1H), 1.74 (s, 9H).

LCMS m/z=312.3 [MH]⁺

Preparation 24 tert-Butyl4-(6-formylpyrazolo[1,5-a]pyrazine-4-yl)-1H-pyrazole-1-carboxylate

A solution of tert-butyl4-(6-vinylpyrazolo[1,5-a]44yrazine-4-yl)-1H-pyrazole-1-carboxylate(Preparation 23; 446 mg, 1.43 mmol) and 2,6-lutidine (767 mg, 7.16 mmol)in 1,4-dioxane (9 mL) and water (3 mL) was cooled to about 0° C., andNaIO₄ (1530 mg, 7.16 mmol) and 4% aq. OSO₄ solution (0.54 mL) wereadded. The mixture was allowed to warm to about 20° C. for about 3 hrs.The solids were removed by filtration and washed with ether. Thecombined 1,4-dioxane and ether were concentrated and the residue waspurified by chromatography to afford the title compound as an off whitesolid (289 mg, 65%).

¹H NMR (400 MHz, CDCl₃) δ: 10.20 (s, 1H), 9.01 (s, 1H), 8.85 (s, 1H),8.50 (s, 1H), 8.30 (d, 1H), 7.08-7.12 (m, 1H), 1.73 (s, 9H).

LCMS m/z=314.2 [MH]⁺

Preparation 25tert-Butyl-4-(6-((hydroxyimino)methyl)45yrazine[1,5-a]45yrazine-4-yl)-1H-pyrazole-1-carboxylate

Hydroxylamine HCl (112 mg, 1.58 mmol) was added to a mixture oftert-butyl4-(6-formylpyrazolo[1,5-a]45yrazine-4-yl)-1H-pyrazole-1-carboxylate(Preparation 24, 450 mg, 1.44 mmol), and Na₂CO₃ (196 mg, 1.58 mmol) inMeOH (20 mL). The mixture was kept at about 20° C. for about 1.5 hrs.The mixture was concentrated, water (30 mL) was added, and the mixturewas stirred for about 5 min before the solid was filtered and dried toyield the title compound as an off white solid (325 mg, 69%).

¹H NMR (400 MHz, CDCl₃) δ: 10.46 (br. s., 1H), 9.53 (s, 1H), 8.81 (s,1H), 8.46 (s, 1H), 8.41 (5, 1 H), 8.19 (d, 1H), 7.03 (d, 1H), 1.73 (s,9H).

LCMS m/z=329.2 [MH]⁺

Preparation 26(3-(4-(1H-Pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)isoxazol-5-yl)methanol

Sodium hypochlorite solution (about 12% to 15%, 0.19 mL about 3.0 mmol)was added dropwise to a solution of tert-butyl(E)-4-(6-((hydroxyimino)methyl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazole-1-carboxylate(Preparation 25, 200 mg, 0.61 mmol) and propargyl alcohol (171 mg, 3.05mmol) in DCM (5 mL) at about 0° C. The mixture was allowed to warm toabout 20° C. for about 18 hrs. The resulting solid was filtered toafford the title compound (115 mg, 67%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.14 (s, 1H), 8.56 (s, 2H), 8.31 (d, 1H),7.50 (d, 1H), 7.09 (s, 1H), 4.57-4.75 (m, 2H).

LCMS m/z=283.1 [MH]⁺

Preparation 27 3-(Cyanomethylene)cyclobutane-1-carbonitrile

A solution of 3-oxocyclobutane-1-carbonitrile* (CAS: 20249-16-5, 14.5 g,152 mmol) in THF (250 mL) was added to a mixture of (EtO)₂P(O)CH₂CN(31.1 g, 175 mmol), LiBr (19.9 g, 229 mmol) and TEA (30.9 g, 305 mmol)in THF (300 mL) at about 25° C. After about 16 hrs, the mixture wasfiltered and the filtrate was concentrated. The residue was purified bychromatography to afford the title compound as a light yellow oil (16.01g, 89%).

*See Synthetic Communications 2005, 35, 657-662.

¹H NMR (400 MHz, CD₃CN) δ: 5.38 (s, 1H), 3.30-3.43 (m, 2H), 3.16-3.30(m, 3H).

LCMS m/z=119.1 [MH]⁺

Example 1(1s,3s)-3-(Cyanomethyl)-3-(4-(6-(5-(hydroxymethyl)isoxazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(cis isomer)

DBU (89.0 mg, 0.58 mmol) was added to a solution of(3-(4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-Aisoxazol-5-Amethanol(Preparation 26; 55.0 mg, 0.19 mmol) and3-(cyanomethylene)cyclobutane-1-carbonitrile (Preparation 27; 23.0 mg,0.19 mmol) in MeCN (4 mL). The reaction was purged with nitrogen andstirred at about 20° C. for about 20 hrs. The mixture was partitionedbetween EtOAc (5 mL) and 1 M aq. NaH₂PO₄ (5 mL). The EtOAc wasseparated, dried (Na₂SO₄), and concentrated. The residue was purifiedchromatography afford the title compound (5 mg, 6%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.26 (m, 1H), 8.92 (m, 1H), 8.54 (m, 1H),8.40 (m, 1H), 7.52 (m, 1H), 7.14 (m, 1H), 5.55 (br s, 1H), 4.70 (s, 2H),3.60 (m, 3H), 3.42-3.45 (m, 2H), 2.78-2.83 (m, 2H).

LCMS m/z=401.4 [MH]⁺

Preparation 28 tert-Butyl3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

To a solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate(CAS 1153949-11-1, 7.00 g, 36.1 mmol) in MeCN (100 mL) was added4-pyrazoleboronic acid pinacol ester (7.71 g, 39.7 mmol) and DBU (2.75g, 18.0 mmol) at about 25° C. After about 18 hrs, the mixture wasconcentrated and the residue was purified column chromatography toafford the title compound as a white solid (11 g, 78%).

¹H NMR (400 MHz, CDCl₃) δ: 7.92 (s, 1H), 7.86 (s, 1H), 4.40 (m, 2H),4.21 (m, 2H), 3.52 (s, 2H), 1.44 (s, 9H), 1.32 (s, 12H).

LC-MS m/z=333.0 [MH-C₄H₈]+

Preparation 29 tert-Butyl3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate

To a solution of tert-butyl3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(Preparation 28, 362 mg, 0.93 mmol) and4,6-dichloropyrazolo[1,5-a]pyrazine (Preparation 4; 167 mg, 0.89 mmol)in 1,4-dioxane (5 mL) was added 2 M aq. K₃PO₄ (1.40 mL) at about 25° C.The mixture was purged with argon for about 2 min andbis(tri-t-butylphosphine)paladium(0) (94.3 mg, 0.184 mmol) was added.The mixture was stirred at about 20° C. for about 2 hrs. The mixture wasdiluted with DCM, separated, and the aqueous phase was extracted twicewith DCM. The combined DCM extracts were dried (Na₂SO₄) andconcentrated. The residue was purified by chromatography to afford thetitle compound as a white solid (295 mg, 75%).

¹H NMR (400 MHz, CDCl₃) δ: 8.42 (s, 1H), 8.41 (s, 1H), 8.31 (s, 1H),8.10 (d, 1H), 7.02 (d, 1H), 4.54 (d, 2H), 4.31 (d, 3H), 3.33 (s, 2H),1.49 (s, 9H).

LCMS m/z=358.1 [MH-C₄H₈]⁺

Preparation 302-(3-(4-(6-Chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylmethyl)azetidin-3-yl)acetonitrile

Part 1

To a solution of tert-butyl3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate(Preparation 29, 0.56 g, 1.35 mmol) in DCM (13.5 mL) was added TFA (7mL) at about 25° C. After about 4 hrs, the mixture was concentrated todryness to afford2-(3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrileas a yellow solid (578 mg, about 100%) which was used without furtherpurification.

Part 2

To a solution of2-(3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile(Part 1, 1.35 mmol) and bromomethylcyclopropane (365 mg, 2.71 mmol) inDMF (13.5 mL) was added TEA (548 mg, 5.41 mmol) at about 25° C. Themixture was heated at about 50° C. for about 14 hrs. The cooled solutionwas diluted with water (20 mL) and extracted with EtOAc (3×20 mL). Thecombined EtOAc extracts were washed with brine (30 mL), dried (Na₂SO₄)and concentrated. The residue was purified by chromatography to affordthe title compound as a yellow solid (314 mg, 63%).

¹H NMR (400 MHz, CDCl₃) δ: 8.39 (s, 1H), 8.37 (s, 1H), 8.27 (s, 1H),8.08 (d, 1H), 7.02 (d, 1H), 3.78-3.84 (m, 2H), 3.59 (d, 2H), 3.42 (s,2H), 2.45 (d, 2H), 0.77-0.87 (m, 1H), 0.48-0.55 (m, 2H), 0.14 (q, 2H).

LCMS m/z=367.9 [MH]⁺ (³⁵Cl isotope)

Preparation 31 Ethyl 3-(tri butylstannyl)-1H-pyrazole-5-carboxylate

Ethynyltributylstannane (50 g, 158 mmol) was added to a solution ofethyldiazoacetate (19.9 g, 175 mmol) in toluene (500 mL) at about 25° C.The solution was heated for about 16 hrs at about 100° C., then wasconcentrated to afford the crude product as a yellow oil (110 g). Thiswas combined with the crude product from an equivalent reaction carriedout with ethynyltributylstannane (22 g, 70 mmol) and ethyldiazoacetate(8.76 g, 77 mmol), and the combined residues were purified by columnchromatography on alumina to afford the title compound as a yellow oil(42 g, 61%).

¹H NMR (400 MHz, CDCl₃) δ: 10.28 (br. s., 1H), 6.84-6.99 (m, 1H), 4.41(q, 2H), 1.47-1.67 (m, 6H), 1.41 (t, 3H), 1.28-1.39 (m, 6H), 1.04-1.24(m, 6H), 0.90 (t, 9H).

LCMS m/z 431.2 [MH]⁺ (¹²⁰Sn isotope).

Preparation 32 (3-(Tributylstannyl)-1H-pyrazol-5-yl)methanol

Ethyl 3-(tributylstannyl)-1H-pyrazole-5-carboxylate (Preparation 31,6000 mg, 13.98 mmol) in THF (200 mL) was added to a stirred suspensionof lithium aluminum hydride (3108 mg, 83.9 mmol) in THF (200 mL) atabout −10° C. After about 4 hrs, the mixture was quenched with Na₂SO₄decahydrate at about −10° C. until effervescence ceased. The mixture wasfiltered and the filter cake was washed with THF (500 mL) and DCM (5×500mL). The combined filtrates were concentrated to afford the titlecompound as a white solid (4460 mg, 82%).

¹H NMR (400 MHz, CDCl₃) δ: 10.35 (br. s., 1H), 6.28-6.43 (m, 1H), 4.75(s, 2H), 1.49-1.60 (m, 6H), 1.29-1.39 (m, 6H), 1.08-1.15 (m, 6H),0.87-0.93 (m, 9H).

LCMS m/z=388.9 [MH]⁺ (¹²⁰Sn isotope)

Example 22-(1-(Cyclopropylmethyl)-3-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

To a solution of2-(3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylmethyl)azetidin-3-yl)acetonitrile(Preparation 30, 204 mg, 0.55 mmol) and3-(tributylstannyl)-1H-pyrazol-5-Amethanol (Preparation 32, 215 mg, 0.55mmol) was added XPhos Pd G2 (43.6 mg, 0.055 mmol) in 1,4-dioxane (5.5mL). The mixture was heated at about 110° C. for about 4 hrs. Themixture was evaporated to dryness and the residue was combined with theresidue from an equivalent reaction using2-(3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylmethyl)azetidin-3-yl)acetonitrile(Preparation 30, 110 mg, 0.27 mmol) and3-(tributylstannyl)-1H-pyrazol-5-Amethanol (Preparation 32, 105 mg, 0.27mmol). The combined residues were purified by HPLC to afford the titlecompound (112 mg, 31%).

¹H NMR (400 MHz, CDCl₃) δ: 8.66 (s, 1H), 8.64-8.69 (m, 1H), 8.38 (s,1H), 8.23 (s, 1H), 8.06 (d, 1H), 6.94 (d, 1H), 6.67 (s, 1H), 4.80 (s,2H), 3.80 (d, 2H), 3.62 (d, 2H), 3.41 (s, 2H), 2.44 (d, 2H), 0.76-0.86(m, 1H), 0.46-0.53 (m, 2H), 0.10-0.16 (m, 2H).

LCMS m/z 430.1 [MH]⁺

Preparation 332-(3-(4-(6-Chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

To a solution of tert-butyl3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate(Preparation 29, 485 mg, 1.17 mmol) in DCM (20 mL) was added TFA (6 mL)at about 0° C. The mixture was stirred at about 25° C. for about 4 hrs.The solution was concentrated. The residue was adjusted to about pH 9with conc. NH₄OH (about 0.5 mL) and partitioned between water (10 mL)and DCM (30 mL). The aqueous solution was extracted with DCM (3×30 mL).The combined DCM extracts were dried (Na₂SO₄) and concentrated to affordthe title compound as a yellow solid (300 mg, 81%).

¹H NMR (400 MHz, CD₃OD) δ: 8.91 (s, 1H), 8.72 (s, 1H), 8.53 (s, 1H),8.20 (d, 1H), 7.40 (d, 1H), 4.90 (d, 2H), 4.66 (d, 2H), 3.72 (s, 2H).

LCMS m/z 313.9 [MH]⁺ (³⁵Cl isotope)

Preparation 342-(3-(4-(6-Chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-ethylazetidin-3-yl)acetonitrile

Sodium acetate (314 mg, 3.82 mmol) and acetaldehyde (842 mg, 19.1 mmol)were added to a solution of2-(3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile(Preparation 33, 120 mg, 0.38 mmol) in MeOH (6 mL) and the mixture wasstirred for about 4 hrs. Then NaBH(OAc)₃ (243 mg, 1.15 mmol) was addedand the mixture was stirred for about 16 hrs longer at about 25° C. Themixture was concentrated and the residue was purified by chromatographyto afford the title compound as a yellow solid (115 mg, 88%).

¹H NMR (400 MHz, CDCl₃) δ: 8.41 (s, 1H), 8.39 (s, 1H), 8.29 (s, 1H),8.10 (d, 1H), 7.04 (d, 1H), 3.79 (d, 2H), 3.59 (d, 2H), 3.43 (s, 2H),2.65 (q, 2H), 1.06 (t, 3H).

LCMS m/z=342.1 [MH]⁺ (Cl³⁵ isotope)

Example 32-(1-Ethyl-3-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

To a solution of2-(3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-ethylazetidin-3-yl)acetonitrile(Preparation 34, 100 mg, 0.29 mmol) in 1,4-dioxane (5 mL) was added3-(tributylstannyl)-1H-pyrazol-5-Amethanol (Preparation 32, 136 mg, 0.35mmol) and XPhos Pd G2 (23.0 mg, 0.029 mmol). The mixture was heated atabout 110° C. for about 16 hrs. The mixture was concentrated and theresidue was purified by chromatography. The product was further purifiedby HPLC to afford the title compound as a yellow solid (59 mg, 46%).

¹H NMR (400 MHz, DMSO-d₆) δ: 13.21 (s, 0.5H), 12.93 (s, 0.5H), 9.23 (s,0.5H), 9.07 (s, 1H), 8.6-8.89 (m, 1H), 8.69 (s, 0.5H), 8.47 (s, 0.5H),8.26 (s, 1H), 7.47-7.53 (m, 1H), 6. −9-6.94 (m, 1H), 5.35 (s, 0.5H),5.35 (s, 0.5H), 4.50-4.57 (m, 2H), 3.68-3.71 (m, 2H), 3.57-3.54 (m, 4H),3.17-3.16 (m, 0.5H), 2.57-2.54 (m, 2H), 0.96-0.93 (m, 3H). This spectrumwas consistent with the presence of distinguishable tautomers.

LCMS m/z=404.3 [MH]⁺

Preparation 35 2-Cyclobutylideneacetonitrile

A mixture of (EtO)₂P(O)CH₂CN (4.48 g, 25.2 mmol), LiBr (1.96 g, 22.6mmol) and TEA (2.28 g, 22.6 mmol) in dry THF (40 mL) was stirred atabout 25° C. for about 2 hrs. To this was added a solution ofcyclobutanone (1.58 g, 22.6 mmol) in THF (5 mL) at about 25° C. Afterabout 16 hrs, the mixture was concentrated and the residue was purifiedby chromatography to afford the title compound as a colorless oil (1.2g, 57%).

¹H NMR (400 MHz, CDCl₃) δ: 5.11 (quin), 2.93-3.05 (m), 2.82-2.92 (m),2.04-2.17 (m).

Preparation 362-(1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile

To a mixture of 2-cyclobutylideneacetonitrile (Preparation 35, 200 mg,2.15 mmol) and 4-pyrazoleboronic acid pinacol ester (458 mg, 2.36 mmol)in MeCN (15 mL) was added DBU (981 mg, 6.44 mmol). The reaction wasstirred at about 25° C. for about 16 hrs and then heated to about 50° C.for about 24 hrs. The mixture was concentrated and the residue waspurified by chromatography to afford the title compound as a colorlessoil (150 mg, 24%).

¹H NMR (400 MHz, CDCl₃) δ: m 7.89 (s, 1H), 7.86 (s, 1H), 3.09 (s, 2H),2.68-2.80 (m, 2H), 2.45-2.55 (m, 2H), 2.01-2.10 (m, 2H), 1.33 (s, 12H).

LCMS m/z=287.9 [MH]⁺

Example 4 2-(1-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile

To a mixture of2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile(Preparation 36, 129 mg, 0.45 mmol) and4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(Preparation 11, 100 mg, 0.43 mmol) in 1,4-dioxane (4.3 mL) was added 2M aq. K₃PO₄ (0.85 mL) and PdCl₂(dppf) (15.7 mg, 0.021 mmol). The mixturewas purged with nitrogen for about 1 min and stirred at about 80° C. forabout 16 hrs. The reaction mixture was combined with an equivalentreaction conducted using2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile(Preparation 36, 20 mg, 0.07 mmol) and4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(Preparation 11, 19. mg, 0.083 mmol), 2 M aq. K₃PO₄ (0.14 mL) andPdCl₂(dppf) (2.5 mg, 0.0035 mmol) in 1,4-dioxane (2 mL). The combinedreaction mixtures were concentrated and the residue was purified bychromatography. The compound was further purified by HPLC to afford thetitle compound as a white solid (22 mg, 12%).

¹H NMR (400 MHz, CD₃OD) δ: 8.68 (s, 1H), 8.63 (s, 1H), 8.39 (s, 1H),8.22 (s, 1H), 8.07 (d, 1H), 8.06 (s, 1H), 7.21 (d, 1H), 3.97 (s, 3H),3.94-3.99 (m, 1H), 3.37 (s, 2H), 3.35-3.39 (m, 1H), 2.84-2.95 (m, 2H),2.54 (ddd, 2H), 2.05-2.21 (m, 2H).

LCMS m/z=358.9 [MH]⁺

Preparation 372-((1r,3s)-1-(4-Bromo-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile(trans isomer)

and

2-((1s,3r)-1-(4-Bromo-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile(cis isomer)

DBU (4.25 mL, 28.4 mmol) was added to a solution of2-(3-methoxycyclobutylidene)acetonitrile (Preparation 90, 3.50 g, 28.4mmol) and 4-bromopyrazole (4.18 g, 28.4 mmol) in MeCN (80 mL) at about25° C. After about 18 hrs, the mixture was poured into NaH₂PO₄ (17.04 g,142 mmol) in water and the phases were separated. The aqueous layer wasextracted twice with EtOAc and the combined EtOAc extracts wereconcentrated. The excess 4-bromopyrazole was removed by chromatographyeluting with DCM:THF (100:0 to 95:5). The material was further purifiedby chromatography eluting with ether:heptane to afford2-((1r,3s)-1-(4-bromo-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrileas a white solid (trans isomer, 2.19 g, 28%)

¹H NMR (400 MHz, CDCl₃) δ: 7.62 (s, 1H), 7.55 (s, 1H), 3.99 (tt, 1H),3.30 (s, 3H), 3.12 (s, 2H), 2.96-3.04 (m, 2H), 2.44-2.51 (m, 2H).

LCMS m/z=270.0 [MH]⁺ (⁷⁹Br isotope)

and2-((1s,3r)-1-(4-bromo-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrileas a colorless oil (cis isomer, 5.00 g, 65%).

¹H NMR (400 MHz, CDCl₃) δ: 7.60 (s, 1H), 7.53 (s, 1H), 4.00 (quin, 1H),3.29 (s, 3H), 2.99 (s, 2H), 2.85-2.96 (m, 2H), 2.56-2.67 (m, 2H).

LCMS m/z=270.0 [MH]⁺ (⁷⁹Br isotope)

Preparation 382-((1r,3s)-3-Methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile

A mixture of2-((1r,3s)-1-(4-bromo-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile(Preparation 37, trans isomer, 3399 mg, 12.58 mmol),bis(pinacolato)diboron (3510 mg, 13.8 mmol) and potassium acetate (3700mg, 37.7 mmol) in 1,4-dioxane (33 mL) was purged with argon for about 5min, followed by the addition of XPhos Pd G2 (1980 mg, 2.52 mmol) atabout 25° C. The mixture was heated at about 65° C. for about 4 hrs. Themixture was concentrated and the residue was purified by chromatographyto afford a solid. To this solid was added EtOAc (10 mL) and heptane (40mL) and the mixture was stirred at about 25° C. for about 30 min. Thesolid was filtered and dried under vacuum to afford the title compoundas a white solid (1.95 g, 49%).

¹H NMR (500 MHz, CDCl₃) δ: 7.91 (s, 1H), 7.87 (s, 1H), 3.98 (tt, 1H),3.28 (s, 3H), 3.17 (s, 2H), 2.98-3.07 (m, 2H), 2.45-2.53 (m, 2H), 1.31(s, 12H).

LCMS m/z=318.0 [MH]⁺

Preparation 392-((1r,3s)-1-(4-(6-Chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile

A solution of2-((1r,3s)-3-methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile(Preparation 38, 1950 mg, 6.15 mmol),4,6-dichloropyrazolo[1,5-a]pyrazine (Preparation 4, 1160 mg, 6.15 mmol)and 2 M aq. K₃PO₄ (9.22 mL) in 1,4-dioxane (25 mL) was purged with argonfor about 5 min followed by the addition ofbis(tri-t-butylphosphine)palladium(0) (157 mg, 0.31 mmol) at about 25°C. After about 2 hrs, the mixture was diluted with EtOAc, the phaseswere separated and the aqueous phase was extracted twice with DCM. Thecombined EtOAc and DCM extracts were dried (Na₂SO₄) and concentrated toafford a solid that was recrystallized from a warm (about 40° C.)mixture of DCM and heptane to afford the title compound as an off-whitesolid (1.12 g, 53%). The filtrate was concentrated and purified bychromatography to afford additional title compound (1.01 g, 47%).

¹H NMR (500 MHz, CDCl₃) δ: m 8.39 (d, 1H), 8.38 (s, 1H), 8.28 (s, 1H),8.09 (d, 1H), 7.03 (dd, 1H), 4.04-4.10 (m, 1H), 3.33 (s, 3H), 3.25 (s,2H), 3.09-3.17 (m, 2H), 2.53-2.61 (m, 2H)

LCMS m/z=343.1 [MH]⁺ (Cl³⁵ isotope)

Preparation 40 3,5-Dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

To a solution of 3,5-dibromopyrazole* (CAS: 67460-86-0, 18.0 g, 79.7mmol) and DHP (30 mL) was added CF₃COOH (73 mg, 0.64 mmol). The mixturewas heated at about 95° C. for about 12 hrs. The reaction was quenchedwith NaOH (96 mg, 2.4 mmol) and then concentrated. The residue waspurified by chromatography to afford the title compound (11.5 g, 46%).

*See: Justus Liebigs Annalen der Chemie 1959, 625, 55-65.

¹H NMR (400 MHz, CDCl₃) δ: 6.35 (s, 1H), 5.42 (d, 1H), 4.05 (m, 1H),3.65 (m, 1H), 2.38-2.48 (m, 1H), 2.11 (m, 1H), 1.90 (m, 1H), 1.62-1.77(m, 3H).

LCMS m/z=226.7 [MH-THP]⁺ (⁷⁹Br, ⁸¹Br isotope)

Preparation 413-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylic acid

n-BuLi (2.5 M, 15.8 mL, 39.5 mmol) was added dropwise to a solution of3,5-dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation 40,9.4 g, 30.0 mmol) in THF (87 mL) at about −78° C. The mixture was keptat about −78° C. for about 2 hrs. A solution of CO₂ (prepared bybubbling CO₂ into anhydrous THF (100 mL) for 20 min at about −70° C. andstirring at that temperature for about 1.5 hrs) was added dropwise whilemaintaining the internal reaction temperature below about −65° C. Themixture was then stirred at about −70° C. for about 1 hr. The mixturewas adjusted to about pH 4 with 1 M aq. HCl at about 0° C. and wasextracted with EtOAc (3×100 mL). The combined EtOAc extracts were washedwith brine (2×50 mL), dried (Na₂SO₄) and concentrated. The residue waspurified by chromatography to afford the title compound as a yellowsolid (5.0 g, 60%).

¹H NMR (400 MHz, DMSO-d₆) δ: 6.99 (s, 1H), 6.17 (dd, 1H), 3.90 (d, 1H),3.49-3.66 (m, 2H), 2.12-2.28 (m, 1H), 1.91-2.04 (m, 1H), 1.83-1.92 (m,1H), 1.58-1.70 (m, 1H), 1.45-1.57 (m, 2H).

Preparation 42 tert-Butyl(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)carbamate

Diphenylphosphoryl azide (10 g, 36.4 mmol) was added to a solution of3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylic acid(Preparation 41, 5 g, 18.17 mmol) and DIPEA (6.4 mL, 37.0 mmol) int-butanol (60.6 mL). The mixture was heated at about 45° C. for about 30min, and then heated under reflux for about 5 hrs. The mixture wasdiluted with EtOAc (300 mL) and washed with saturated aq. NaHCO₃ (3×100mL), brine (2×100 mL), dried (Na₂SO₄) and concentrated. The residue waspurified by chromatography to afford the title compound as a lightyellow oil (3.36 g, 53%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.64 (br. s., 1H), 6.26 (s, 1H), 5.44 (dd,1H), 3.84 (d, 1H), 3.55-3.70 (m, 1H), 2.08-2.20 (m, 1H), 1.91-2.00 (m,1H), 1.75 (dd, 1H), 1.54-1.64 (m, 1H), 1.48-1.53 (m, 2H), 1.46 (s, 9H).

LCMS m/z=367.9 [MNa]⁺ (⁷⁹Br isotope)

Preparation 433-Bromo-1-(tetrahydro-2H-pyran-2-yl)-5-(diBoc)-amino-1H-pyrazole

DMAP (27 mg, 0.22 mmol) was added to a solution of tert-butyl(3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)carbamate(Preparation 42, 390 mg, 1.13 mmol), di-tert-butyl dicarbonate (492 mg,2.25 mmol) and TEA (0.47 mL, 3.38 mmol) in DCM (4 mL) at about 20° C.After about 18 hrs, the mixture was concentrated and the residue waspurified by chromatography to afford the title compound (450 mg, 89%)

¹H NMR (400 MHz, CDCl₃) δ: 6.42 (s, 1H), 5.15 (m, 1H), 4.02 (m, 1H),3.60 (m, 1H), 2.40 (m, 1H), 2.15 (m, 1H), 1.88 (m, 1H), 1.58-1.76 (m,3H), 1.48 (s, 18H).

LCMS m/z=467.9 [MNa]⁺ (⁷⁹Br isotope)

Preparation 442-((1r,3s)-1-(4-(6-(5-(DiBoc)-amino-1-(tetrahydro-2H-pyran-2-yl)-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile

A mixture of KOAc (110 mg, 1.06 mmol), bis(pinacolato)diboron (164 mg,0.64 mmol),3-bromo-1-(tetrahydro-2H-pyran-2-yl)-5-(diBoc)-amino-1H-pyrazole(Preparation 43, 191 mg, 0.43 mmol) and XPhos Pd G2 (55 mg, 0.07 mmol)in 1,4-dioxane (3.5 mL) was was heated to about 65° C. for about 3.5hrs. The mixture was cooled to about 25° C. and2-((1r,3s)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxy-cyclobutyl)acetonitrile(Preparation 39, 68 mg, 0.20 mmol) was added and the mixture was purgedwith nitrogen before 2 M aq. K₃PO₄ (0.53 mL, 1.06 mmol) and XPhos Pd G2(55 mg, 0.07 mmol) were added. The mixture was heated at about 80° C.for about 3 hrs. The reaction was quenched with brine and extracted withEtOAc. The EtOAc extract was concentrated and the residue was purifiedby chromatography to afford the title compound as a yellow solid (91 mg,32%).

¹H NMR (400 MHz, CDCl₃) δ: 9.08 (s, 1H), 8.39 (s, 1H), 8.33 (s, 1H),8.09 (d, 1H), 6.97 (d, 1H), 6.90 (s, 1H), 5.26 (dd, 1H), 4.02-4.11 (m,2H), 3.64 (t, 1H), 3.34 (s, 3H), 3.25 (s, 2H), 3.12-3.20 (m, 2H),2.55-2.62 (m, 2H), 2.17-2.25 (m, 1H), 1.93 (dd, 1H), 1.58-1.82 (m, 4H),1.45 (s, 18H).

LCMS m/z=674.5 [MH]⁺

Preparation 452-((1r,3s)-1-(4-(6-(5-Amino-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile

TFA (2 mL) was added to2-((1r,3s)-1-(4-(6-(5-(diBoc)-amino-1-(tetrahydro-2H-pyran-2-yl)-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)-acetonitrile(Preparation 44, 91 mg, 0.13 mmol) in anhydrous DCM (1 mL) at about 20°C. After about 1 hr, the mixture was concentrated. DCM was added,followed by saturated aq. NaHCO₃ until the solution pH became basic. Thephases were separated and the aqueous phase was extracted twice withDCM. The combined DCM extracts were dried (Na₂SO₄), concentrated, andthe residue was purified by chromatography to afford the title compound(50 mg, 95%).

¹H NMR (400 MHz, CDCl₃) δ: 8.53 (s, 1H), 8.40 (s, 1H), 8.25 (s, 1H),8.06 (s, 1H), 6.96 (br. s., 1H), 6.01 (br. s., 1H), 4.33 (br. s., 1H),4.05 (m, 1H), 3.31 (s, 3H), 3.25 (s, 2H), 3.11 (dd, 2H), 2.55 (dd, 2H).

LCMS m/z=390.3 [MH]⁺

Example 5N-(3-(4-(1-((1r,3s)-1-(Cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazol-5-yl)acetamide

2-((1r,3s)-1-(4-(6-(5-Amino-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxy-cyclobutyl)acetonitrile(Preparation 45, 39 mg, 0.1 mmol) was placed in a reaction tube, whichwas then evacuated and backfilled three times with nitrogen. To this wasadded anhydrous DCM (1 mL). The tube was cooled to about 0° C. beforeN-methylmorpholine (11 mg, 0.11 mmol) and acetyl chloride (8.6 mg, 0.11mmol) were added. The mixture was allowed to warm to about 25° C. overabout 18 hrs. The mixture was concentrated and the residue was dissolvedin MeOH (2 mL). K₂CO₃ (30 mg, 0.22 mmol) was added at about 0° C. Afterabout 3 hrs, the mixture was filtered through Celite®. The filtrate wasconcentrated and the residue was purified by chromatography to affordthe title compound (30 mg, 63%).

¹H NMR (400 MHz, CD₃OD) δ: 8.80 (s, 1H), 8.75 (s, 1H), 8.40 (s, 1H),8.09 (d, 1H), 7.23 (d, 1H), 6.88 (s, 1H), 4.02-4.12 (m, 1H), 3.81 (s,3H), 3.34 (s, 2H), 3.15-3.24 (m, 2H), 2.48-2.59 (m, 2H), 2.21 (s, 3H).

LCMS m/z=432.2 [MH]⁺

Preparation 46 Ethyl5-(4-(1-((1r,3s)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazole-3-carboxylate

A solution of2-((1r,3s)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile(Preparation 39, 200 mg, 0.58 mmol) and ethyl3-(tributylstannyl)-1H-pyrazole-5-carboxylate (Preparation 31, 300 mg,0.70 mmol) in 1,4-dioxane (5.8 mL) was purged with nitrogen and XPhos PdG2 (45.9 mg, 0.058 mmol) added at about 25° C. The reaction was heatedat about 80° C. for about 16 hrs. The cooled mixture was purified bychromatography to afford the title compound as a yellow solid (220 mg,84%).

¹H NMR (400 MHz, DMSO-d₆) δ: 14.09 (s, 1H), 9.39 (s, 1H), 9.10 (s, 1H),8.72 (s, 1H), 8.30 (d, 1H), 7.59 (d, 1H), 7.53 (d, 1H), 4.33 (q, 2H),4.01 (dd, 1H), 3.44 (s, 3H), 3.22 (s, 2H), 3.14-3.20 (m, 2H), 2.43-2.48(m, 2H), 1.34 (t, 3H).

LCMS m/z=447.2 [MH]⁺

Example 65-(4-(1-((1r,3s)-1-(Cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-N-methyl-1H-pyrazole-3-carboxamide

A solution of ethyl5-(4-(1-((1r,3s)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazole-3-carboxylate(Preparation 46, 100 mg, 0.22 mmol) in 30% MeNH₂ in EtOH solution (35mL) was sealed in a microwave tube at about 20° C. After about 16 hrs,the mixture was concentrated and the residue was purified by HPLC toafford the title compound as a white solid (62 mg, 58%).

¹H NMR (400 MHz, CD₃OD) δ: 9.00 (s, 1H), 8.91 (s, 1H), 8.57 (s, 1H),8.18 (s, 1H), 7.37 (br. s., 1H), 7.26 (s, 1H), 4.61 (s, 1H), 4.04-4.15(m, 1H), 3.37 (s, 3H), 3.33 (s, 2H), 3.18-3.26 (m, 2H), 2.95 (s, 3H),2.56 (dd, 2H).

LCMS m/z=432.1 [M+H]⁺

Preparation 47 tert-Butyl3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

To a vial were added4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(Preparation 11, 150 mg), tert-butyl3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(Preparation 28, 374 mg, 0.96 mmol), 2 M aq. Na₂CO₃ (0.96 mL) and1,4-dioxane (4 mL). The mixture was purged with argon for about 5 min,followed by the addition of PdCl₂(dppf) (93.7 mg, 0.13 mmol). Themixture was heated at about 120° C. for about 1 hr under microwaveirradiation. The mixture was diluted with EtOAc, washed with water,dried (Na₂SO₄), and concentrated. The residue was purified bychromatography to afford the title compound as a yellow solid (233 mg,79%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.03 (s, 1H), 8.95 (s, 1H), 8.53 (s, 1H),8.37 (s, 1H), 8.20 (d, 1H), 8.16 (s, 1H), 7.46 (s, 1H), 4.54 (d, 2H),4.25 (d, 3H), 3.91 (s, 3H), 3.67 (s, 2H), 1.42 (s, 9H).

LCMS m/z=460.2 [MH]⁺

Preparation 482-(3-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

TFA (1 mL) was added to tert-butyl3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(Preparation 47, 233 mg, 0.51 mmol) in DCM (5 mL) at about 25° C. Afterabout 90 min, the mixture was concentrated. The residue was concentratedtwice with toluene, then dried under vacuum. The residue was dissolvedin MeOH and passed through a bed of polymer supported carbonate resin.The eluted solution was concentrated to afford the title compound (200mg, about 100%) which was used without further purification.

¹H NMR (400 MHz, DMSO-d₆) δ: 9.12 (s, 1H), 9.06 (s, 1H), 8.58 (s, 1H),8.39 (s, 1H), 8.22 (d, 1H), 8.17 (s, 1H), 7.50 (d, 1H), 4.68-4.77 (m,2H), 4.35-4.40 (m, 2H), 3.93 (s, 2H), 3.91 (s, 3H).

LCMS m/z=360.5 [MH]⁺

Example 72,2′-(3-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1,3-diyl)diacetonitrile

DIPEA (132 μl, 0.76 mmol) was added to a solution of2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acet-onitrile(Preparation 48, 91 mg, 0.25 mmol) in DMF (2 mL). Bromoacetonitrile (36mg, 0.30 mmol) was added at about 25° C. After about 18 hrs, thereaction was quenched with conc. NH₄OH and stirred at about 25° C. forabout 10 min. The mixture was concentrated and the residue was dilutedwith DCM. The DCM was washed twice with saturated aq. NH₄Cl, then twicewith saturated aq. Na₂CO₃. The DCM was dried (Na₂SO₄) and concentrated.The residue was .purified by chromatography to afford the title compoundas an off white solid (68 mg, 68%).

¹H NMR (400 MHz, CD₃OD) δ: 8.77 (s, 1H), 8.74 (s, 1H), 8.45 (s, 1H),8.25 (s, 1H), 8.08-8.10 (m, 2H), 7.25 (d, 1H), 4.01 (d, 2H), 3.98 (s,3H), 3.86 (d, 2H), 3.78 (s, 2H), 3.54 (s, 2H)

LCMS m/z=399.3 [MH]⁺

Example 82-(3-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-(methylsulfonyl)azetidin-3-yl)acetonitrile

To a solution of2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile(Preparation 48, 120 mg, 0.27 mmol) and TEA (331 mg, 3.27 mmol) in DCM(20 mL) was added methanesulfonyl chloride (313 mg, 2.73 mmol) at about0° C. The mixture was then stirred at about 10° C. for about 1 hr beforebeing concentrated. The residue was purified using HPLC to afford thetitle compound as a white solid (39 mg, 33%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.05 (s, 1H), 8.99 (s, 1H), 8.57 (s, 1H),8.37 (s, 1H), 8.21 (d, 1H), 8.17 (s, 1H), 7.47 (d, 1H), 4.65 (d, 2H),4.30 (d, 2H), 3.91 (s, 3H), 3.70 (s, 2H), 3.14 (s, 3H).

LCMS m/z=437.9 [MH]⁺

Example 92-(1-(Cyclopropylsulfonyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

To a mixture of2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile(Preparation 48, 100 mg, 0.25 mmol) in DCM (10 mL) were added TEA (153mg, 1.52 mmol) and cyclopropanesulfonyl chloride (107 mg, 0.76 mmol) atabout 0° C. The mixture was stirred at about 20° C. for about 16 hrs,then concentrated. The residue was purified by HPLC to afford the titlecompound as a white solid (60 mg, 46%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.05 (s, 1H), 9.00 (s, 1H), 8.57 (s, 1H),8.37 (s, 1H), 8.21 (d, 1H), 8.16 (s, 1H), 7.46 (d, 1H), 4.69 (d, 2H),4.32 (d, 2H), 3.91 (s, 3H), 3.70 (s, 2H), 2.85 (m, 1H), 0.96-1.09 (m,4H).

LCMS m/z=464.0 [MH]⁺

Example 102-(3-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-propionylazetidin-3-yl)acetonitrile

To a solution of2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile(Preparation 48, 90 mg, 0.23 mmol) in DCM (5 mL) were added TEA (69 mg,0.68 mmol) and propionic anhydride (59 mg, 0.45 mmol). The reaction wasstirred at about 20° C. for about 30 min, then concentrated and theresidue was purified by HPLC to afford the title compound as a whitesolid (28 mg, 30%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.05 (s, 1H), 8.97 (s, 1H), 8.55 (s, 1H),8.37 (s, 1H), 8.21 (d, 1H), 8.16 (s, 1H), 7.46 (d, 1H), 4.80 (d, 1H),4.52 (dd, 2H), 4.23 (d, 1H), 3.91 (s, 3H), 3.70 (s, 2H), 2.16 (q, 2H),0.99 (t, 3H).

LCMS m/z 416.0 [MH]⁺

Preparation 49 2-(3-(Benzyloxy)cyclobutylidene)acetonitrile

LiBr (0.270 g, 3.12 mmol) was placed under vacuum, then backfilled withnitrogen and THF (28 mL) was added, followed by (EtO)₂POCH₂CN (0.53 mL,3.12 mmol) and TEA (0.79 mL, 5.67 mmol). The resulting solution wasstirred at about 20° C. for about 45 min, then a solution of3-(benzyloxy)cyclobutanone (500 mg, 2.84 mmol) in dry THF (3 mL) wasadded. After about 5 hrs, the mixture was poured into EtOAc (100 mL) andthe EtOAc was washed three times with saturated aq. NH₄Cl (3×50 mL) andwith brine (25 mL). The EtOAc extract was dried (MgSO₄) andconcentrated. The residue was chromatographed to afford the titlecompound (480 mg, 85%).

¹H NMR (400 MHz, CDCl₃) δ: 7.29-7.43 (m, 5H), 5.24 (quin, 1H), 4.45-4.53(m, 2H), 4.19 (quin, 1H), 3.18-3.29 (m, 1H), 3.03-3.13 (m, 1H),2.86-3.00 (m, 2H).

Preparation 50 2-(3-Hydroxycyclobutyl)acetonitrile

Palladium hydroxide on carbon (20% Pd, wet, 430 mg) was added to asolution of 2-(3-(benzyloxy)cyclobutylidene)acetonitrile (Preparation49, 430 mg, 2.16 mmol) in THF (6.5 mL). The mixture was pressurizedunder hydrogen (100 psi) in a steel reactor and stirred at about 20° C.for about 1 hr. Additional palladium hydroxide on carbon (20% Pd, wet,430 mg) added and the mixture was re-pressurized under hydrogen (100psi) and stirred for about 1.5 hrs longer. The mixture was diluted withEtOAc, filtered through Celite®, and the filtrate was concentrated toafford the title compound as a colorless oil (240 mg, 100%) as a mixtureof cis and trans isomers.

Isomer 1-(400 MHz, CDCl₃) δ: 4.52 (quin, 1H), 2.63-2.74 (m, 2H),2.19-2.28 (m, 4H), 2.07-2.17 (m, 1H), 1.83 (br. s, 1H).

Isomer 2: ¹H NMR (400 MHz, CDCl₃) δ: 4.14-4.25 (m, 1H), 2.55-2.64 (m,2H), 2.48 (dd, 4H), 1.83 (br. s, 1H), 1.67-1.79 (m, 1H).

Preparation 51 2-(3-Oxocyclobutyl)acetonitrile

To a solution of 2-(3-hydroxycyclobutyl)acetonitrile (Preparation 50, 50mg, 0.45 mmol) in dry THF (1.8 mL) was added Dess-Martin periodinane(CAS: 87413-09-0, 216 mg, 0.49 mmol). The vial was sealed under ambientatmosphere and stirred at about 50° C. for about 2 hrs. The mixture wasdiluted with Et₂O (10 mL) followed by saturated aq. NaHCO₃ (4 mL).Sodium thiosulfate pentahydrate (954 mg, 3.82 mmol) was added and themixture was stirred vigorously for about 10 min until all solids haddissolved. The phases were separated and the aqueous phase extractedonce more with Et₂O. The combined Et₂O extracts were dried (MgSO₄) andconcentrated. The residue was purified by chromatography to afford thetitle compound as a colorless oil (27 mg, 55%).

¹H NMR (400 MHz, CDCl₃) δ: 3.23-3.37 (m, 2H), 2.89-3.01 (m, 2H),2.75-2.89 (m, 1H), 2.69 (d, 2H).

¹³C NMR (101 MHz, CDCl₃) δ: 203.6, 117.6, 52.3, 23.1, 20.6.

Preparation 52 2-(3-(Cyanomethyl)cyclobutylidene)acetonitrile

The title compound was prepared (75 mg, 89%) using the method ofPreparation 35 using 2-(3-oxocyclobutyl)acetonitrile (Preparation 51, 70mg, 0.64 mmol), (EtO)₂POCH₂CN (213 mg, 1.15 mmol), LiBr (100 mg, 1.15mmol) and TEA (0.27 mL, 1.92 mmol). The title compound was used directlyin the next reaction (Example 11 and 12).

¹H NMR (400 MHz, CDCl₃) δ: 5.25 (m, 1H), 3.10-3.30 (m, 2H), 2.80 (m,3H), 2.60 (m, 2H).

GCMS m/z=132 [M]⁺

Preparation 536-(1-Methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

Pd(dppf)Cl₂ (5.01 g, 6.85 mmol) was added a mixture of4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(Preparation 11, 8 g, 34 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(12.1 g, 41.1 mmol) and 2 M aq. K₂CO₃ (34.2 mL) in 1,4-dioxane (30 mL)and toluene (30 mL) at about 10° C. while a stream of nitrogen wasbubbled through the solution. The mixture was stirred at about 100° C.for about 16 hrs, then kept at about 10° C. for about 48 hrs. Themixture was filtered and the filtrate was concentrated. The residue waspurified by chromatography to afford the title compound as a grey oil(6.3 g, 69%).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.97 (s, 1H), 8.72 (s, 1H), 8.40 (s, 1H),8.35 (s, 1H), 8.15 (d, 1H), 8.12 (s, 1H), 7.36 (d, 1H), 3.91 (s, 3H).

LCMS m/z=265.8 [MH]⁺

Example 112,2′-((1s,3s)-1-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1,3-diyl)diacetonitrile(cis isomer)

and

Example 122,2′-((1r,3r)-1-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1,3-diyl)diacetonitrile(trans isomer)

DBU (34 mg, 0.22 mmol) was added to a slurry of2-(3-(cyanomethyl)cyclobutylidene)acetonitrile (Preparation 52, 32 mg,0.24 mmol) and6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(Preparation 53, 53 mg, 0.20 mmol) in MeCN (4.8 mL). The mixture washeated at about 50° C. for about 16 hours, then concentrated. Theresidue was purified by chromatography to afford a mixture of the titlecompounds as 1:1 mixture of cis/trans isomers (80 mg, 83%). The isomerswere separated by HPLC to afford2,2′-((1s,3s)-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1,3-diyl)diacetonitrileas a solid (cis isomer, 27 mg, 36%).

¹H NMR (500 MHz, 9:1 CDCl₃-CD₃OD) δ: 8.45 (s, 1H), 8.35 (s, 1H), 8.25(s, 1H), 7.99 (d, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 6.93 (s, 1H), 3.95(s, 3H), 3.72 (s, 2H), 3.18 (s, 2H), 2.81-2.91 (m, 2H), 2.72-2.81 (m,1H), 2.72-2.81 (m, 1H), 2.64-2.72 (m, 2H), 2.61 (d, 2H).

LCMS m/z=399.1 [MH]

and 2,2′-((1r,3r)-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclo-butane-1,3-diyl)diacetonitrileas a solid (trans isomer, 14 mg, 18%).

¹H NMR (500 MHz, CDCl₃) δ: 8.49 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H),8.05 (d, 1H), 7.96 (m, 2H), 6.95 (d, 1H), 4.00 (s, 3H), 3.75 (br. s.,1H), 3.15-3.25 (m, 2H), 3.11 (s, 2H), 2.88 (tt, 1H), 2.64 (d, 2H),2.48-2.59 (m, 2H).

LCMS m/z=399.1 [MH]

Preparation 54 2-(3-(Benzyloxy)cyclobutylidene)acetonitrile

To a solution of (EtO)₂P(O)CH₂CN (24.1 g, 136 mmol) in dry THF (500 mL)was added LiBr (11.8 g, 136 mmol) and TEA (18.4 g, 182 mmol) and theresulting mixture was stirred at about 20° C. for about 1 hr. To thiswas added 3-(benzyloxy)cyclobutan-1-one (16.00 g, 90.8 mmol). Themixture was stirred at about 20° C. for about 20 hrs. The mixture wasfiltered and the filtrate was concentrated. The residue was purified bychromatography to afford the title compound as a pale yellow liquid (18g, 99%).

¹H NMR (400 MHz, CDCl₃) δ: 7.29-7.40 (m, 5H), 5.24 (dt, 1H), 4.45-4.53(m, 2H), 4.19 (quin, 1H), 3.19-3.29 (m, 1H), 3.03-3.13 (m, 1H),2.86-3.00 (m, 2H).

LCMS m/z=200.1 [MH]⁺

Preparation 552-(3-(Benzyloxy)-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile(mixture of cis and trans isomers)

DBU (1.448 g, 9.4 mmol) was added to a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(Preparation 53, 313 mg, 1.18 mmol) and2-(3-(benzyloxy)cyclobutylidene)acetonitrile (Preparation 54, 470 mg,2.36 mmol) in MeCN (6.38 mL). The mixture was stirred at about 20° C.for about 18 hrs, then it was poured into aq. NaH₂PO₄ solution tomaintain a pH of about 5. The mixture was extracted three times withDCM. The combined DCM extracts were concentrated and the residue waspurified by chromatography to afford the title compound (474 mg, 86%).

¹H NMR (400 MHz, CD₃OD) δ: 8.67-8.72 (m, 2H), 8.63 (s, 1H), 8.39 (s,1H), 8.22 (s, 1H), 8.04-8.10 (m, 2H), 7.25-7.42 (m, 5H), 4.53 (s, 2H),4.24-4.34 (m, 1H), 3.97 (s, 3H), 3.29 (s, 2H), 2.92-3.02 (m, 2H),2.77-2.88 (m, 2H).

LCMS m/z=465.3 [MH]⁺

Example 132-((1s,3r)-3-Hydroxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile(cis isomer)

and

Example 14 PF-068779002-((1r,3s)-3-Hydroxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile(trans isomer)

Sodium iodide was dried with a heating gun at full heat for 5 min thencooled to about 25° C. under nitrogen prior to use. The dried NaI (1.21g, 8.1 mmol) was added at about 20° C. to a stirred solution of(2-(3-(benzyloxy)-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile(Preparation 55, 377 mg, 0.81 mmol) in MeCN (12 mL), followed by TMSCl(1.05 mL, 8.1 mmol). The mixture was stirred at about 50° C. for about18 hrs. An additional portion of both NaI and TMSCl were added and themixture was maintained at about 50° C. for about 8 hrs additional. Thecooled mixture was poured into ice cold saturated aq. NaHCO₃ containingsodium thiosulfate pentahydrate (10.1 g, 40.6 mmol) and extracted threetimes with EtOAc. The combined EtOAc extracts were concentrated toafford a mixture of the two title compounds. This mixture was purifiedby chromatography to afford 2-((is,3r)-3-hydroxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile(trans isomer, 80 mg, 26%)

¹H NMR (400 MHz, CD₃OD) δ: 8.72 (s, 1H), 8.71 (s, 1H), 8.42 (s, 1H),8.24 (s, 1H), 8.05-8.10 (m, 2H), 7.24 (d, 1H), 4.34-4.44 (m, 1H), 3.98(s, 3H), 3.35 (s, 2H), 3.22-3.28 (m, 2H), 2.49 (dd, 2H).

LCMS m/z=375.4 [MH]⁺

and 2-((1r,35)-3-hydroxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile(cis isomer, 180 mg, 59%).

¹H NMR (400 MHz, CD₃OD) δ: 8.67 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H),8.21 (s, 1H), 8.07 (d, 1H), 8.05 (s, 1H), 8.04-8.06 (m, 1H), 7.21 (d,1H), 4.41 (quin, 1H), 3.97 (s, 3H), 3.28 (s, 2H), 2.95-3.04 (m, 2H),2.68-2.78 (m, 2H).

LCMS m/z=375.4 [MH]⁺

Example 152-((1r,3s)-3-Methoxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile(trans isomer)

and

Example 162-((1s,3r)-3-Methoxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile(cis isomer)

A solution of a mixture of24(1s,3r)-3-hydroxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrileand2-((1r,3s)-3-Hydroxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile(Examples 13 and 14, mixture of cis and trans isomers, 48 mg, 0.13 mmol)in THF (0.2 mL) was sequentially treated with tetrabutylammonium bromide(TBAB, 126 mg, 0.38 mmol), 1 M aq. NaOH (1.02 mL) and dimethyl sulfate(6 μL). The reaction vial was sealed and stirred vigorously at about 20°C. for about 1 hr. Additional dimethyl sulfate (14 μL) and TBAB (10 mg)were added and the reaction was kept at about 20° C. for about 2 hrs.The mixture was extracted three times with EtOAc and the combined EtOAcextracts were dried (Na₂SO₄) and concentrated. The residue was purifiedby chromatography to afford a mixture of cis and trans isomers. Furtherpurification by HPLC afforded24(1r,3s)-3-methoxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrileas a solid (trans isomer, 10 mg, 20%)

¹H NMR (400 MHz, CD₃CN) δ: 8.61 (d, 1H), 8.55 (s, 1H), 8.38 (s, 1H),8.12 (s, 1H), 8.05 (d, 1H), 7.99 (s, 1H), 7.13 (d, 1H), 3.99-4.08 (m,1H), 3.93 (s, 3H), 3.27 (s, 5H), 3.13-3.21 (m, 2H), 2.45-2.53 (m, 2H).

LCMS m/z=389.1 [MH]⁺

and 2-((1s,3r)-3-methoxy-1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrileas a solid (cis isomer, 17 mg, 33%).

¹H NMR (400 MHz, CD₃CN) δ: 8.60 (d, 1H), 8.49 (s, 1H), 8.36 (s, 1H),8.12 (s, 1H), 8.04 (d, 1H), 7.98 (s, 1H), 7.12 (dd, 1H), 4.03 (quin,1H), 3.92 (s, 3H), 3.26 (s, 3H), 3.19 (s, 2H), 2.89-2.97 (m, 2H),2.65-2.74 (m, 2H).

LCMS m/z=389.1 [MH]⁺

Preparation 56 Benzyl (R)-2-methyl-3-oxoazetidine-1-carboxylate

Part 1

A solution of N,4-dimethyl-N-nitrosobenzenesulfonamide (Diazald®, 21.25g, 99.19 mmol) in Et₂O (150 mL) was added dropwise to a solution of KOH(6 g, 106.9 mmol) and 2-(2-ethoxyethoxy)ethanol (30 mL) and water (10mL) at about 70° C. The mixture was heated at about 70° C. and anethereal solution of diazomethane was collected as a yellow liquid bydistillation (100 mL, estimated to contain 66 mmol of diazomethane)using a dry-ice/acetone condenser and used immediately in Part 2.

Part 2

Ethyl chloroformate (2.430 g, 22.4 mmol) was added drop wise to asolution of Cbz-D-alanine (5.00 g, 22.4 mmol) and TEA (2.27 mg, 22.4mmol) in THF (50 mL) at about −15° C. The reaction mixture was warmed toabout 0° C. and the diazomethane solution from Part 1 (100 mL, about 66mmol) was added dropwise and stirred at about 20° C. for about 16 hrs.The reaction mixture was quenched with water (10 mL) and extracted withEtOAc (2×30 mL). The combined EtOAc extracts were dried (Na₂SO₄) andconcentrated. The residue was purified by chromatography to afford thediazo-ketone intermediate (4.5 g, 81%) as a white solid. The materialwas used in Part 3.

Part 3

To a solution of the diazo-ketone intermediate of Part 2 (4.50 g, 18.2mmol) in DCM (450 mL) were added TEA (18 mg, 0.18 mmol) and Rh₂(OAc)₄(40 mg, 0.091 mmol) at about 0° C. The mixture was stirred for about 16hrs at about 25° C. The mixture was quenched with water (50 mL) and theDCM phase was separated and concentrated. The residue was purified bychromatography on afford the title compound as a white solid (1.20 g,30%).

¹H NMR (400 MHz, CDCl₃) δ: 7.34-7.38 (m, 5H), 5.18 (m, 2H), 5.03 (m,1H), 4.65-4.81 (m, 2H), 1.49 (d, 3H).

GCMS m/z=219 [M]⁺

Preparation 57 Benzyl(R)-3-(cyanomethylene)-2-methylazetidine-1-carboxylate

To a mixture of LiBr (166 mg, 1.92 mmol) and TEA (277 mg, 2.74 mmol) inTHF (10 mL) was added (EtO)₂P(O)CH₂CN (339 mg, 1.92 mmol) at about 25°C. After about 2.5 hrs, benzyl (R)-2-methyl-3-oxoazetidine-1-carboxylate(Preparation 56, 300 mg, 1.37 mmol) in THF (2 mL) was added at about 25°C. and the mixture was stirred for about 16 hrs. The mixture wasconcentrated and the residue was purified by chromatography to affordthe title compound as mixture of E/Z olefin isomers as colorless oil(290 mg, 87%).

¹H NMR (400 MHz, CDCl₃) δ: 7.33-7.40 (m, 5H), 5.36 (m, 1H), 5.10-5.17(m, 2H), 4.97 (m, 1H), 4.63-4.77 (m, 2H), 1.50-1.67 (m, 3H).

Preparation 58 Benzyl(2R)-3-(cyanomethyl)-2-methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

To a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(Preparation 53, 268 mg, 1.01 mmol) in MeCN (15 mL) were added benzyl(R)-3-(cyanomethylene)-2-methylazetidine-1-carboxylate (Preparation 57,294 mg, 1.21 mmol) and DBU (77 mg, 0.51 mmol) at about 15° C. Themixture was stirred at about 25° C. for about 7 hrs before being dilutedwith EtOAc (50 mL) and washed with 1 M aq. citric acid (15 mL) followedby brine (15 mL). The EtOAc extract was concentrated and the residue waspurified by chromatography to afford the title compound as a yellow gum(500 mg, 97%).

¹H NMR (400 MHz, CDCl₃) δ: 8.49 (s, 1H), 8.33 (s, 1H), 8.32 (s, 1H),8.05 (d, 1H), 7.96 (s, 1H), 7.95 (s, 1H), 7.33-7.40 (m, 5H), 6.93 (d,2H), 5.15 (s, 2H), 4.87 (m, 1H), 4.61 (d, 1H), 4.26 (d, 1H), 4.01 (s,3H), 3.27 (s, 2H), 1.69 (d, 3H).

LCMS m/z=530.1 [M+Na]⁺

Preparation 592-((2R)-2-Methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

To a mixture of NaI (2.36 g, 15.8 mmol) in MeCN (16 mL) was added TMSCl(2 mL, 15.8 mmol) at about 0° C. The mixture was stirred at about 15° C.for about 4 hrs. A solution of benzyl(2R)-3-(cyanomethyl)-2-methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate(Preparation 58, 400 mg, 0.79 mmol) in MeCN (4 mL) was added at about 0°C. Stirring was continued at about 15° C. for about 3 hrs. The mixturewas cooled to about 10° C. and quenched by the addition of TEA (2 mL).The mixture was concentrated. The residue was dissolved in EtOAc (20 mL)and MeOH (2 mL) and the solids present were removed by filtration. Thefiltrate was concentrated and the residue was purified by TLC to affordthe title compound as a yellow solid (200 mg, 68%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.06 (s, 1H), 9.03 (s, 1H), 8.59 (s, 1H),8.39 (s, 1H), 8.22 (d, 1H), 8.16 (s, 1H), 7.47 (s, 1H), 5.09 (m, 1H),4.74 (d, 1H), 4.24 (d, 1H), 3.91 (s, 3H), 2.99 (s, 2H), 1.65 (d, 3H).

LCMS m/z=374.0 [MH]⁺

Example 172-((2R,3S)-2-Methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl)acetonitrile

To a solution of2-((2R)-2-methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile(Preparation 59, 200 mg, 0.43 mmol) in DMF (5 mL) were added2,2,2-trifluoroethyl trifluoromethanesulfonate (298 mg, 1.29 mmol) andDIPEA (332 mg, 2.57 mmol). The mixture was stirred at about 10° C. forabout 36 hrs before being diluted with EtOAc (30 mL) and washed withbrine (15 mL). The EtOAc extract was concentrated the residue waspurified by HPLC to afford the title compound as a mixture ofdiastereomers (80 mg, 41%) as a white solid. Further HPLC purificationafforded the title compound as a white solid (41.8 mg, 21%, 94.7% ee).

¹H NMR (400 MHz, CD₃CN) δ: 8.59 (s, 1H), 8.45 (s, 1H), 8.36 (s, 1H),8.10 (s, 1H), 8.04 (d, 1H), 7.98 (s, 1H), 7.09-7.13 (m, 1H), 3.92-3.96(m, 1H), 3.91 (s, 3H), 3.84-3.89 (m, 1H), 3.77-3.84 (m, 1H), 3.38 (s,2H), 3.28-3.43 (m, 1H), 3.15 (dq, 1H), 1.36 (d, 3H).

LCMS m/z=456.2 [MH]⁺

Example 182-((1r,3r)-1-(4-(6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(1H-pyrazol-5-yl)cyclobutyl)acetonitrile

To a solution of LiBr (70 mg, 0.81 mmol), TEA (205 μL, 1.47 mmol) in THF(10 mL), was added (EtO)₂P(O)CH₂CN (143 mg, 0.81 mmol). The mixture wasstirred at about 20° C. for about 30 min.3-(1H-Pyrazol-5-yl)cyclobutan-1-one (Preparation 99, 100 mg, 0.74 mmol)was added and mixture was kept at about 20° C. for about 18 hrs. About30% of the reaction solution was taken out and6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(Preparation 53, 58 mg, 0.22 mmol) and DBU (110 μL, 0.73 mmol) in MeCN(5 mL) were added. Stirring at about 20° C. was maintained for about 20hrs. The mixture was concentrated and the residue was purified bychromatography to afford the title compound (6 mg, 6%).

¹H NMR (500 MHz, CD₃OD) δ: 8.85 (s, 1H), 8.73 (s, 1H), 8.46 (s, 1H),8.26 (s, 1H), 8.10 (s, 2H), 7.60 (br. s., 1H), 7.28 (d, 1H), 6.32 (d,1H), 3.95-4.04 (m, 3H), 3.69-3.78 (m, 1H), 3.33-3.43 (m, 2H), 2.77-2.89(m, 2H).

LCMS m/z=425.4 [MH]⁺

Example 19(1s,3s)-3-(Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

To a solution of(1s,35)-3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(Preparation 91, 539 mg, 1.72 mmol) and4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(Preparation 11, 350 mg, 1.5 mmol) in 1,4-dioxane (7.5 mL) was added 2 Maq. K₃PO₄ (2.25 mL) at about 25° C. The mixture was placed undernitrogen, then XPhos Pd G2 (11.8 mg, 0.0150 mmol) was added. The mixturewas heated at about 40° C. for about 6 h, then it was heated to about80° C. to dissolve the precipitated product. The aqueous layer wasremoved while maintaining the temperature at about 80° C., then the1,4-dioxane phase was added to EtOH (70 mL, previously preheated toabout 50° C.). The mixture was stirred for about 10 min at about 50° C.before being removed from heat. Stirring at about 25° C. was continuedfor about 18 h. The solid was filtered and washed with EtOH (2×25 mL)and dried under vacuum to afford the title compound as a white solid(483 mg, 84%).

mp 217-220° C.

¹H NMR (400 MHz, DMSO-d₆) δ: 9.02 (s, 1H), 8.87 (s, 1H), 8.51 (s, 1H),8.37 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 7.45 (s, 1H), 3.92 (s, 3H),3.65-3.59 (m, 1H), 3.57 (s, 2H), 3.26-3.16 (m, 2H), 2.88 (m, 2H).

¹³C NMR (101 MHz, DMSO-d₆) δ: 145.21, 142.50, 140.09, 137.15, 133.80,131.39, 129.54, 129.24, 121.94, 121.03, 120.33, 117.69, 114.55, 99.94,59.62, 39.28, 36.90, 27.42, 14.64.

LCMS m/z=384.2 [MH]⁺

Example 20(1r,3r)-3-(Cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

To a solution of(1r,3r)-3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(Preparation 91, 3.38 g, 10.8 mmol) and4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(Preparation 11, 2.20 g, 9.4 mmol) in 1,4-dioxane (47.1 mL) was added 2M aq. K₃PO₄ (14.1 mL). Nitrogen was bubbled through the mixture forabout 5 min at about 25° C., then XPhos Pd G2 (37.0 mg, 0.047 mmol) wasadded.

The mixture was heated at about 40° C. for about 18 h, then it washeated to about 80° C. to dissolve the precipitated product. The aqueouslayer was removed while maintaining the temperature at about 80° C.,then the 1,4-dioxane phase was added to EtOH (471 mL, previouslypreheated to about 50° C.). The mixture was stirred for about 10 min atabout 50° C. before being removed from heat. Stirring at about 25° C.was continued for about 6 h. The solid was filtered and washed with EtOH(2×25 mL), water (2×50 mL), and EtOH (2×25 mL). The precipitate wasdried under vacuum to afford the title compound as a white solid (3.61g, 74%). The title compound (500 mg, 1.30 mmol) was heated in1,4-dioxane (6.5 mL) at about 80° C. until all of the material wasdissolved. 1,2-Bis(diphenylphosphino)ethane (7.8 mg, 0.019 mmol) wasadded and heating at about 80° C. was continued for about 4 hrs, thenthe 1,4-dioxane phase was added to EtOH (58.7 mL, previously preheatedto about 50° C.). An additional 6.5 mL of preheated EtOH was used torinse the reaction vessel. The mixture was removed from heat. Stirringat about 25° C. was continued for about 18 h. The solid was filtered andwashed with EtOH (2×5 mL), water (5 mL), then EtOH (3×5 mL). Theprecipitate was dried under vacuum to afford the title compound as awhite solid (450 mg, 90%).

Melting point 213-215° C.

¹H NMR (400 MHz, DMSO-d₆) δ: 9.02 (s, 1H) 8.92 (s, 1H) 8.52 (s, 1H) 8.37(s, 1H) 8.19 (s, 1H) 8.16 (s, 1H) 7.45 (s, 1H) 3.91 (s, 3H) 3.55-3.65(m, 1H) 3.52 (s, 2H) 3.22-3.38 (m, 2H) 2.85-3.00 (m, 2H).

¹³C NMR (126 MHz, DMSO-d₆) δ: 145.17, 142.46, 140.20, 137.13, 133.78,131.38, 129.82, 129.51, 122.28, 121.13, 120.33, 117.30, 114.54, 99.91,61.51, 39.26, 36.26, 29.65, 16.05.

LCMS m/z=384.1 [MH]⁺.

Preparation 60(1r,3r)-3-(Cyanomethyl)-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(trans isomer)

and

(1s,3s)-3-(Cyanomethyl)-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(cis isomer)

To a solution of3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(600 mg, 2.88 mmol) and 3-(cyanomethylene)cyclobutane-1-carbonitrile(Preparation 27, 341 mg, 2.88 mmol) in MeCN (28.8 mL) was added DBU (439mg, 2.88 mmol) at about 20° C. After about 18 hrs at about 20° C., themixture was poured into EtOAc and 10% aq. K₂HPO₄. The EtOAc wasseparated and the aqueous phase was extracted twice more with EtOAc. Thecombined EtOAc extracts were washed with brine, dried (Na₂SO₄) andconcentrated. The residue was purified by column chromatography toafford(1r,3r)-3-(cyanomethyl)-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(trans isomer, 325 mg, 35%) ¹H NMR (400 MHz, CDCl₃) δ: 7.79 (s, 1H),3.17-3.28 (m, 3H), 3.16 (s, 2H), 2.81-2.89 (m, 2H), 2.39 (s, 3H), 1.32(s, 12H).

LCMS m/z=327.2 [MH]⁺

and (1s, 3s)-3-(cyanomethyl)-3-(3-methyl-4-(4,4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (cisisomer, 171 mg, 18%).

¹H NMR (400 MHz, CDCl₃) δ: 7.75 (s, 1H), 3.18-3.28 (m, 1H), 3.08-3.18(m, 2H), 3.05 (s, 2H), 2.93-3.02 (m, 2H), 2.39 (s, 3H), 1.32 (s, 12H).

LCMS m/z=327.2 [MH]⁺

Example 21(1r,3r)-3-(Cyanomethyl)-3-(3-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

To a solution of(1r,3r)-3-(cyanomethyl)-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(Preparation 60, trans isomer, 209 mg, 0.64 mmol) in 1,4-dioxane (4.3mL) was added4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(Preparation 11, 150 mg, 0.64 mmol) and 2 M aq. K₃PO₄ (0.96 mL). Themixture was purged with nitrogen for about 5 min, then XPhos Pd G2 (101mg, 0.13 mmol) was added. The mixture was heated at about 40° C. forabout 2 hrs, then concentrated. The residue was dissolved in EtOAc andthe EtOAc was washed with water. The aqueous phase was extracted twicemore with EtOAc, then once with DCM. The combined EtOAc and DCM extractswere dried (Na₂SO₄), concentrated, and the residue was purified bychromatography to afford a solid which was recrystallized from MeCN toafford the title compound (120 mg, 47%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.00 (s, 1H), 8.74 (s, 1H), 8.26 (s, 1H),8.18 (s, 1H), 8.08 (s, 1H), 7.32 (s, 1H), 3.91 (s, 3H), 3.55 (quin, 1H),3.48 (s, 2H), 3.22-3.30 (m, 2H), 2.84-2.93 (m, 2H), 2.63 (s, 3H).

LCMS m/z=398.3 [MH]⁺

Preparation 614-Bromo-1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole

To a solution of 4-bromo-1-methyl-1H-pyrazole-3-methanol (720 mg, 3.77mmol) in THF (30 mL) was added DHP (951 mg, 11.3 mmol) and PTSA (14 mg,0.075 mmol). The solution was stirred at about 50° C. for about 16 hrs.The mixture was concentrated and the residue was purified bychromatography to afford the title compound as a colorless oil (1.0 g,84%).

¹H NMR (400 MHz, CDCl₃) δ: 7.37 (s, 1H), 4.81 (t, 1H), 4.74 (d, 1H),4.46 (d, 1H), 3.96-4.03 (m, 1H), 3.88 (s, 3H), 3.56-3.63 (m, 1H),1.80-1.93 (m, 1H), 1.59-1.78 (m, 3H), 1.48-1.57 (m, 2H).

LCMS m/z=190.7 [MH-THP]⁺

Preparation 62(1s,3s)-3-(Cyanomethyl)-3-(4-(6-(1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

Part 1

To a solution of4-bromo-1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole(Preparation 61, 200 mg, 0.73 mmol) in 1,4-dioxane (10 mL) were addedKOAc (313 mg, 3.19 mmol), and bis(pinacolato)diboron (405 mg, 1.59mmol). The mixture was purged with nitrogen for about 5 min before theaddition of Pd(dppf)Cl₂ (78 mg, 0.11 mmol). The mixture was heated atabout 90° C. for about 18 hrs. The mixture was concentrated to afford animpure sample of1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleas a black oil (234 mg), which was used in Part 2 below without furtherpurification.

Part 2

A mixture of(1r,3r)-3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile(Preparation 75, 85 mg, 0.25 mmol),1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4, 5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazole (Part 1, 81 mg, 0.25mmol), and 2 M aq. K₃PO₄ (1.0 mL) in 1,4-dioxane (3.0 mL) was purgedwith argon for about 2 min, after which XPhos Pd G2 (39 mg, 0.050 mmol)was added. The reaction mixture was heated at about 45° C. for about 45min. The 1,4-dioxane phase was separated from the aqueous phase, whichwas extracted further with EtOAc (5 mL). The combined 1,4-dioxane andEtOAc extracts were dried (Na₂SO₄) and concentrated. The residue whichwas purified by chromatography to afford the title compound (50 mg,40%).

¹H NMR (400 MHz, CDCl₃) δ: 8.92 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H),8.07-8.10 (m, 1H), 8.00 (s, 1H), 6.96 (d, 1H), 5.02 (d, 1H), 4.87-4.91(m, 1H), 4.70 (m, 1H), 4.59 (d, 1H), 4.51 (d, 1H), 3.99 (s, 3H),3.51-3.62 (m, 2H), 3.34-3.44 (m, 1H), 3.29 (s, 2H), 2.99 (m, 2H),1.80-1.96 (m, 3H), 1.68-1.80 (m, 3H).

LCMS m/z=498.3 [MH]⁺

Example 22(1r,3r)-3-(Cyanomethyl)-3-(4-(6-(3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

PTSA (10 mg, 0.052 mmol) was added to solution of(1s,3s)-3-(cyanomethyl)-3-(4-(6-(1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(Preparation 62, 50 mg, 0.10 mmol) in MeOH (10 mL). The reaction mixturewas kept at about 20° C. for about 18 hrs. The precipitated solid wasfiltered to afford the title compound (20 mg, 48%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.00 (s, 1H), 8.91 (s, 1H), 8.48 (s, 1H),8.35 (s, 1H), 8.22 (d, 1H), 7.47 (d, 1H), 5.41 (br. s., 1H), 4.66 (s,2H), 3.88 (s, 3H), 3.54-3.62 (m, 1H), 3.52 (s, 2H), 3.28-3.34 (m, 2H),2.90-2.98 (m, 2H).

LCMS m/z=414.4 [MH]⁺

Preparation 63(1r,3r)-3-(Cyanomethyl)-3-(4-(6-(1-methyl-3-nitro-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

Part 1

To a solution of 4-bromo-1-methyl-3-nitro-1H-pyrazole (200 mg, 0.97mmol) in 1,4-dioxane (10 mL) were added KOAc (285 mg, 2.90 mmol), andbis(pinacolato)diboron (368 mg, 1.45 mmol). The mixture was purged withnitrogen for about 5 min, after which Pd(dppf)Cl₂ (70.8 mg, 0.097 mmol)was added. The mixture was heated at about 90° C. for about 18 h. Themixture was concentrated to afford impure1-methyl-3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleas a black oil, which was used without further purification in Part 2.

Part 2

A mixture of (1r,3r)-3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile(Preparation 75, 130 mg, 0.38 mmol),1-methyl-3-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Part 1, 97 mg, 0.38 mmol), and 2 M aq. K₃PO₄ (2.0 mL) in 1,4-dioxane(6.0 mL) was purged with argon for about 2 min, after which XPhos Pd G2(60.6 mg, 0.077 mmol) was added. The mixture was heated at about 45° C.for about 45 min. The 1,4-dioxane phase was separated from the aqueousphase, which was extracted further with EtOAc (10 mL). The combined1,4-dioxane and EtOAc extracts were dried (Na₂SO₄) and concentrated. Theresidue was purified by chromatography to afford the title compound (120mg, 72%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.10 (s, 1H), 8.90 (s, 1H), 8.56 (s, 1H),8.43 (s, 1H), 8.32 (d, 1H), 7.56 (br. s., 1H), 4.05 (s, 3H), 3.54-3.60(m, 1H), 3.51 (s, 2H), 3.18-3.29 (m, 2H), 2.88-2.98 (m, 2H).

LCMS m/z=429.4 [MH]⁺

Example 23(1r,3r)-3-(4-(6-(3-Amino-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile

To a solution of(1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-3-nitro-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(Preparation 63, 120 mg, 0.28 mmol) in EtOH (3 mL) and water (0.5 mL)were added NH₄Cl (90 mg, 1.68 mmol) and iron powder (50 mg, 0.90 mmol).The reaction was stirred at about 60° C. for about 18 hrs, after whichadditional portions of iron powder and NH4Cl were added. The mixture washeated at about 100° C. for about 3 hrs. The mixture was concentratedand hot EtOH (20 mL) was added. The undissolved solids were removed byfiltration. The filtrate was concentrated and the residue was purifiedby chromatography to afford the title compound as a white solid (10 mg,9%).

¹H NMR (400 MHz, CD₃OD) δ: 8.74 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H),8.08 (d, 1H), 7.94 (s, 1H), 7.24 (d, 1H), 3.77 (s, 3H), 3.47-3.55 (m,1H), 3.43 (s, 2H), 3.34-3.41 (m, 2H), 2.98 (dd, 2H).

LCMS m/z=399.4 [MH]⁺

Preparation 64 3,5-Dibromo-1-methyl-1H-pyrazole

A solution of 3,5-dibromopyrazole (6.5 g, 28.7 mmol) in THF (30 mL) wasadded dropwise to an ice-cooled suspension of NaH (2.88 g, 60% inmineral oil, 71.9 mmol) in THF (45 mL). The mixture was stirred at about0° C. for about 1 hrs. Iodomethane (5.37 mL, 86.3 mmol) was added andthe mixture was stirred at about 0° C. for about 3 hrs, then stirringwas continued at about 15° C. for about 2 hrs. The mixture was pouredinto saturated aq. NH₄Cl (20 mL) and extracted with EtOAc (40 mL). TheEtOAc extract was washed with brine (20 mL), dried (Na₂SO₄), andconcentrated. The residue was purified by chromatography to afford thetitle compound as a colorless oil (5.5 g, 79%).

¹H NMR (400 MHz, CDCl₃) δ: 6.31 (s, 1H), 3.87 (s, 3H).

LCMS m/z=240.6 [MH]⁺ (⁷⁹Br, ⁸¹Br isotope)

Preparation 65 3-Bromo-1-methyl-1H-pyrazole-5-carboxylic acid

A solution of 3,5-dibromo-1-methyl-1H-pyrazole (Preparation 64, 3.0 g,12.5 mmol) Era THF (30 mL) was treated dropwise with n-BuLi (2.5 M, 6.25mL, 15.6 mmol) at about −70° C. After about 30 min at this temperature,a solution of CO₂ in THF (30 mL) was added dropwise while maintainingthe internal temperature below about −65° C. The mixture was stirred atthis temperature for about 1 hrs. The reaction mixture was then pouredinto 1 M aq. HCl (50 mL) and the mixture was partially concentrated toremove most of the THF. The aqueous layer was extracted with DCM (50mL). The DCM extract was dried (Na₂SO₄) and concentrated to afford thetitle compound as a yellow solid (2.1 g, 81%).

¹HNMR (400 MHz, DMSO-d₆) δ: 13.70 (br s, 1H), 6.95 (s, 1H), 4.04 (s,3H).

LCMS m/z=206.9 [MH]⁺ (⁸¹Br isotope)

Preparation 66 tert-Butyl (3-bromo-1-methyl-1H-pyrazol-5-yl)carbamate

Diphenylphosphoryl azide (18.8 g, 68.5 mmol) was added to a solution of5-bromo-2-methyl-2H-pyrazole-3-carboxylic acid (Preparation 65, 7.02 g,34.2 mmol) and DIPEA (11.9 mL, 68.5 mmol) in t-butanol (114 mL). Themixture was stirred at about 45° C. for about 30 min, then heated underreflux for about 5 hrs. The cooled mixture was diluted with EtOAc (60mL) and washed with saturated aq. NaHCO₃ (2×30 mL) and brine (20 mL).The EtOAc extract was concentrated and the residue was purified bychromatography to afford the title compound as a yellow solid (4.80 g,51%).

¹H NMR (400 MHz, DMSO-d₆) δ: 6.28 (br s, 1H), 6.18 (s, 1H), 3.73 (s,3H), 1.50 (s, 9H).

LCMS m/z=221.7 [MH-C₄H₈]⁺ (⁸¹Br isotope)

Preparation 67 3-Bromo-1-methyl-5-(diBoc)-amino-1H-pyrazole

Di-tert-butyl dicarbonate (1.58 g, 7.24 mmol) was added to a solution oftert-butyl (3-bromo-1-methyl-1H-pyrazol-5-yl)carbamate (Preparation 66,2.0 g, 7.24 mmol), TEA (4.04 mL, 29.0 mmol), and DMAP (177 mg, 1.45mmol) in DCM (40 mL). The mixture was stirred at about 20° C. for about18 hrs. Water (25 mL) was added and the mixture was extracted with DCM(2×30 mL). The combined DCM extracts were concentrated and the residuewas purified chromatography to afford the title compound (1.85 g, 67)%.

¹H NMR (400 MHz, CDCl₃) δ: 6.06-6.20 (m, 1H), 3.64 (s, 3H), 1.44 (s,18H).

LCMS m/z=378.2 [MH]⁺ (⁸¹Br isotope)

Example 242-((1r,3s)-1-(4-(6-(5-Amino-1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile

Part 1

A mixture of 3-bromo-1-methyl-5-(diBoc)-amino-1H-pyrazole (Preparation67, 1200 mg, 3.19 mmol), KOAc (988 mg, 9.57 mmol) andbis(pinacolato)diboron (1210 mg, 4.78 mmol) in 1,4-dioxane (15 mL) waspurged with argon for about 5 minutes before XPhos Pd G2 (502 mg, 0.64mmol) was added. The reaction mixture was heated at about 65° C. forabout 3.5 hrs, then 2-((is,3r)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclo-butyl)acetonitrile(Preparation 100, 1090 mg, 3.19 mmol), 2 M aq. K₃PO₄ (4.78 mL) and XPhosPd G2 (502 mg, 0.64 mmol) were added. The mixture was purged with argonagain, then heated at about 80° C. for about 1 hrs. EtOAc was added andthe phases were separated. The aqueous phase was extracted twice morewith EtOAc and the combined EtOAc extracts were concentrated. Theresidue was purified by chromatography to afford a mixture of mono- anddi-BOC intermediates (710 mg, 36%) which was used in Part 2.

Part 2

TFA (6 mL, 80 mmol) added to a solution of the mono- and di-BOCintermediates of Part 1 (710 mg, 1.18 mmol) in DCM (6 mL) at about 20°C. After about 1 hrs, the mixture was concentrated. DCM was added,followed by sufficient saturated aq. NaHCO₃ to render the solution pHbasic. The phases were separated and the aqueous phase was extractedtwice more with DCM. The combined DCM extracts were dried (Na₂SO₄) andconcentrated. An equivalent reaction using the compound of Part 1 (220mg, 0.36 mmol) and TFA (2 mL, 30 mmol) in DCM (2 mL) was combined withthe material from the reaction above and the combined samples werepurified by chromatography to afford the title compound as a clear gum(470 mg, 99%).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.81 (s, 1H), 8.73 (s, 1H), 8.40 (s, 1H),8.21 (d, 1H), 7.44 (d, 1H), 5.33 (br. s, 2H), 3.94-4.02 (m, 1H), 3.62(s, 3H), 3.44 (s, 2H), 3.21 (s, 3H), 3.14-3.20 (m, 2H), 2.39-2.45 (m,2H).

LCMS m/z=404.5 [MH]⁺

Preparation 68 Diethyl 4-bromo-1H-pyrazole-3,5-dicarboxylate

A mixture of 1H-pyrazole-3,5-dicarboxylic acid diethyl ester (4.0 g,18.85 mmol) and N-bromosuccinimide (4.03 g, 22.6 mmol) in a mixture ofconc. nitric acid and glacial acetic acid (12.0 mL, 5:95 v/v) was heatedby microwave irradiation at about 120° C. for about 20 minutes. A totalof total of 13.0 g (61.26 mmol) of 1H-pyrazole-3,5-dicarboxylic aciddiethyl ester starting material was processed in this manner in parallelbatches. The resulting brown crude reaction mixtures were combined,poured into water (260 mL), and treated with sufficient NaHCO₃ to renderthe solution pH basic. The mixture was extracted with EtOAc (3×300 mL).The combined EtOAc extracts were dried (Na₂SO₄) and concentrated toafford the title compound as an off-white solid (17.0 g, 95%).

¹H NMR (400 MHz, CDCl₃) δ: 8.79 (br. s., 1H), 4.44 (q, 4H), 1.42 (t,6H).

LCMS m/z=290.7 [MH]⁺ (⁷⁹Br isotope)

Preparation 69 Diethyl4-bromo-1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate

A solution of 4-bromo-1H-pyrazole-3,5-dicarboxylic acid diethyl ester(Preparation 68, 9.66 g, 33.18 mmol) and2-bromo-1-(1-methyl-1H-pyrazol-4-yl)-ethanone (Preparation 6, 6.0 g,29.55 mmol) in MeCN (140 mL) was treated with K₂CO₃ (5.31 g, 38.40 mmol)and the reaction mixture was stirred at about 25° C. for about 16 hrs.Water (100 mL) was added and the mixture was extracted with EtOAc (3×100mL). The combined EtOAc extracts were dried (Na₂SO₄) and concentrated.The residue was purified by chromatography to afford the title compoundas a white solid (10.0 g, 82%).

¹HNMR (400 MHz, CDCl₃) δ: 7.95 (s, 1H), 7.92 (s, 1H), 5.82 (s, 2H), 4.43(q, 2H), 4.36 (q, 2H), 3.96 (s, 3H), 1.45 (t, 3H), 1.35 (t, 3H).

LCMS m/z=436.8 [MNa]⁺ (⁸¹Br isotope)

Preparation 70 Diethyl4-methyl-1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate

A mixture of K₂CO₃ (11.0 g, 79.9 mmol) and4-bromo-1H-[2-(1-methyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-1H-pyrazole-3,5-dicarboxylicacid diethyl ester (Preparation 69, 11.0 g, 26.62 mmol) in DMF (133.0mL) was purged with nitrogen at about 25° C., after which Pd(dppf)Cl₂(1950 mg, 2.66 mmol) and trimethylboroxine (10.0 g, 79.9 mmol) wereadded and the solution was heated at about 110° C. for about 5 hrs. Thecooled reaction was diluted with EtOAc (100 mL) and the resultingmixture was washed with brine (2×100 mL), dried (Na₂SO₄), andconcentrated. The residue was purified by chromatography to afford thetitle compound as a yellow solid (5.45 g, 50%).

¹H NMR (400 MHz, CDCl₃) δ: 7.92 (s, 1H), 7.90 (s, 1H), 5.78 (s, 2H),4.41 (q, 2H), 4.28 (q, 2H), 3.95 (s, 3H), 2.58 (s, 3H), 1.39 (t, 3H),1.31 (t, 3H).

LCMS m/z=348.9 [MH]⁺

Preparation 71 Ethyl4-hydroxy-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate

4-Methyl-[2-(1-methyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-1H-pyrazole-3,5-dicarboxylicacid diethyl ester (Preparation 70, 5.35 g, 15.36 mmol) was mixed withdry EtOH (15 mL) and concentrated. The resulting solid was dissolved inEtOH (40 mL) and NH₄OAc (3.55 g, 46.1 mmol) was added. The reactionmixture was heated at about 130° C. in an autoclave for about 8 hrs.After cooling, the mixture was filtered and the precipitate was dried toafford the title compound as an off-white solid (3.40 g, 73%).

¹H NMR (400 MHz, DMSO-d₆) δ: 11.45 (br. s., 1H), 8.27 (s, 1H), 8.08 (s,1H), 8.02 (s, 1H), 4.31 (m, 2H), 3.87 (s, 3H), 2.61 (s, 3H), 1.24-1.40(m, 3H).

LCMS m/z=301.8 [MH]⁺

Preparation 724-Hydroxy-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyrazine-2-carboxylicacid

Lithium hydroxide monohydrate (1.42 g, 33.9 mmol) was added to asuspension of4-hydroxy-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyrazine-2-carboxylicacid ethyl ester (Preparation 71, 3.40 g, 11.3 mmol) in THF (50 mL),MeOH (50 mL) and water (25 mL). The mixture was stirred at about 60° C.for about 4 hrs. The cooled mixture was concentrated and water (50 mL)was added. The pH of the mixture was adjusted to about 2 by the additionof 12 M aq. HCl. The resulting precipitate was filtered and washed withwater (50 mL), then dried under vacuum to afford the title compound as asolid.

¹HNMR (400 MHz, DMSO-d₆) δ: 12.90-13.20 (br. s, 1H), 11.40 (s, 1H), 8.30(s, 1H), 8.02 (m, 2H), 3.90 (s, 3H), 2.60 (s, 3H).

LCMS m/z=301.8 [MH]⁺, 323.8 [MNa]⁺

Preparation 733-Methyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyrazin-4-ol

4-Hydroxy-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyrazine-2-carboxylicacid (Preparation 72, 2.58 g, 9.44 mmol) was added in portions topreheated sulfolane (18.9 mL) at about 280° C. Once the addition wascomplete, the mixture was stirred for an additional 1 hrs at about 280°C. The cooled mixture was purified directly by chromatography on silicagel (eluting with petroleum ether: EtOAc (100:0 to 50:50), then DCM:MeOH(91:9)) to afford the title compound as a yellow solid (1.50 g, 69%).

¹HNMR (400 MHz, DMSO-d₆) δ: 11.20 (s, 1H), 8.38 (s, 1H), 8.02 (s, 1H),7.96 (s, 1H), 7.70 (s, 1H), 3.85 (s, 3H), 2.40 (s, 3H).

Preparation 744-Chloro-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyrazine

To a suspension of3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyrazin-4-ol(Preparation 73, 1.40 g, 6.11 mmol) in MeCN (60.0 mL) was added POCl₃(4.68 g, 30.5 mmol). The reaction mixture was heated at about 80° C. forabout 16 hrs. After cooling, the mixture was poured into water (200 mL)at about 25° C. The mixture was adjusted to about pH 9 by the additionof saturated aq. NaHCO₃ (200 mL), then extracted with EtOAc (5×100 mL).The combined EtOAc extracts were dried (Na₂SO₄) and concentrated. Theresidue was purified by chromatography, then further purified by HPLC toafford the title compound as a white solid (163 mg, 11%).

¹H NMR (400 MHz, CDCl₃) δ: 8.37 (s, 1H), 7.89 (s, 1H), 7.85 (s, 1H),7.80 (s, 1H), 3.96 (s, 3H), 2.57 (s, 3H). LCMS m/z=247.7 [MH]⁺ (Cl³⁵isotope)

Example 25(1r,3r)-3-(Cyanomethyl)-3-(4-(3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

To a solution of4-chloro-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyrazine(Preparation 74, 98 mg, 0.40 mmol) and(1r,3r)-3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(Preparation 91, 247 mg, 0.79 mmol) in 1,4-dioxane (9 mL) was added 2 Maq. K₃PO₄ (0.59 mL) at about 25° C. and the mixture was purged withnitrogen for about 2 min before XPhos Pd G2 (62.3 mg, 0.079 mmol) wasadded. The mixture was purged with nitrogen for about 3 min, then heatedat about 80° C. for about 16 hrs. The mixture was filtered andconcentrated. The residue was purified by chromatography, then furtherpurified by HPLC to afford the title compound as a light yellow solid(56 mg, 36%).

¹H NMR (400 MHz, DMSO-d₆): δ: 8.98 (s, 1H), 8.94 (s, 1H), 8.60 (s, 1H),8.27 (s, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 3.90 (s, 3H),3.52-3.57 (m, 3H), 3.19-3.26 (m, 2H), 2.91-2.97 (m, 2H), 3.06 (s, 3H).

LCMS m/z=398.0 [MH]⁺

Preparation 75(1r,3r)-3-(4-(6-Chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile

A mixture of 4,6-dichloropyrazolo[1,5-a]pyrazine (Preparation 4, 350 mg,1.86 mmol),(1r,3r)-3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile,(Preparation 91, trans isomer, 581 mg, 1.86 mmol), and 2 M aq. K₃PO₄(2.79 mL) in 1,4-dioxane (10 mL) was purged with argon for about 5 min,after which bis(tri-t-butylphosphine)palladium(0) (48.0 mg, 0.093 mmol)was added. The mixture was kept at about 25° C. for about 2 hrs thenfiltered. The precipitate was washed with Et₂O and dried. The filtratewas concentrated, triturated with Et₂O, filtered, washed with Et₂O anddried. The two precipitates were combined to afford the title compoundas a white solid (605 mg, 96%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.05 (d, 1H), 8.93 (s, 1H), 8.46 (s, 1H),8.32 (d, 1H), 7.61 (d, 1H), 3.55-3.62 (m, 1H), 3.54 (s, 2H), 3.24-3.32(m, 2H), 2.89-3.00 (m, 2H). LCMS m/z=338.2 [MH]⁺

Example 26(1r,3r)-3-(Cyanomethyl)-3-(4-(6-(5-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

Part 1

A mixture of (1r,3r)-3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile(Preparation 75, 85 mg, 0.25 mmol),3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 93, 73 mg, 0.25 mmol),and 2 M aq. K₃PO₄ (1.0 mL) in 1,4-dioxane (3.0 mL) was purged with argonfor about 2 min, after which XPhos Pd G2 (39.6 mg, 0.050 mmol) wasadded. The mixture was heated at about 45° C. for about 45 min beforebeing cooled and concentrated. The residue was purified bychromatography to afford(1r,3r)-3-(cyanomethyl)-3-(4-(6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(26 mg, 22%), which was used directly in Part 2.

LCMS m/z=384.3 [MH-THP]⁺

Part 2

TFA (1 mL) was added to a solution of(1r,3r)-3-(cyanomethyl)-3-(4-(6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(26 mg, 0.055 mmol) in DCM (2 mL). The reaction mixture was heated toabout 50° C. for about 1 hrs. The mixture was concentrated and theresidue was concentrated twice with toluene (5 mL each time). Theresidue was then purified by chromatography to afford a solid, which wasfurther triturated with ether to afford the title compound (8 mg, 38%).

¹H NMR (400 MHz, CD₃CN) δ: 8.87 (s, 1H), 8.66 (s, 1H), 8.48 (s, 1H),8.15 (d, 1H), 7.23 (s, 1H), 6.73 (s, 1H), 3.46 (dd, 1H), 3.36 (s, 2H),3.32-3.41 (m, 2H), 2.98 (dd, 2H), 2.37 (s, 3H). LCMS m/z=384.4 [MH]⁺

Example 27 2-((1s,3r)-1-(4-(6-(5-(Hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile

A solution of2-((1s,3r)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile(Preparation 82, 100 mg, 0.29 mmol), and(3-(tributylstannyl)-1H-pyrazol-5-yl)methanol (Preparation 32, 113 mg,0.29 mmol) in 1,4-dioxane (2 mL) was purged with argon for 5 min,followed by the addition of XPhos Pd G2 (45.9 mg, 0.058 mmol). Themixture was heated at about 80° C. for about 18 hrs. The resultingprecipitate was filtered, washed with 1,4-dioxane and Et₂O, and dried toafford the title compound as a white solid (62 mg, 53%).

¹H NMR (400 MHz, CD₃CN) δ: 8.86 (s, 1H), 8.58 (s, 1H), 8.44 (s, 1H),8.13 (d, 1H), 7.21 (d, 1H), 6.85 (s, 1H), 4.65 (d, 2H), 4.05 (quin, 1H),3.27 (s, 3H), 3.21 (s, 2H), 2.90-2.99 (m, 2H), 2.67-2.76 (m, 2H).

LCMS m/z=405.3 [MH]⁺

Example 282-((1r,3s)-1-(4-(6-(5-(Hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile

A solution of2-((1r,3s)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile(Preparation 39; 1000 mg, 2.92 mmol) and(3-(tributylstannyl)-1H-pyrazol-5-Amethanol (Preparation 32, 1130 mg,2.92 mmol) in 1,4-dioxane (2 mL) was purged with argon for 5 min,followed by the addition of XPhos Pd G2 (45.9 mg, 0.058 mmol). Themixture was heated at about 80° C. for about 18 hrs. The precipitate wasfiltered and then purified by chromatography to afford an off whitesolid. The solid was heated in sufficient boiling EtOH until it wasentirely dissolved, and then stirred for about 18 hrs at about 20° C.The precipitate was filtered and dried under vacuum to afford the titlecompound as a crystalline solid (507 mg, 43%).

¹H NMR (400 MHz, CD₃CN) δ: 11.48 (br. s.), 8.89 (s), 8.65 (s), 8.46 (s),8.15 (d), 7.23 (s), 6.87 (s), 4.67 (d), 4.08 (quin), 3.31 (s), 3.30 (s),3.15-3.25 (m), 2.53 (dd).

LCMS m/z=405.3 [MH]⁺

Preparation 76 Ethyl 5-(tri butylstannyl)isoxazole-3-carboxylate

TEA (0.69 mL, 4.95 mmol) was added dropwise to an ice-cold solution ofethyl 2-chloro-2-(hydroxyimino)acetate (500 mg, 3.30 mmol) andethynyltributylstannane (1040 mg, 3.30 mmol) in Et₂O (10 mL). Thereaction mixture was warmed to about 20° C. and kept for about 18 hrs.The mixture was concentrated and the residue was purified bychromatography to afford the title compound as a colorless oil (810 mg,57%).

¹H NMR (400 MHz, CDCl₃) δ: 6.80 (s, 1H), 6.77-6.84 (m, 1H), 4.45 (q,2H), 1.51-1.63 (m, 6H), 1.43 (t, 3H), 1.34 (dq, 6H), 1.15-1.26 (m, 6H),0.90 (t, 9H).

LCMS m/z=454.2 [MNa]⁺ (¹²⁰Sn isotope)

Preparation 77 Ethyl5-(4-(1-((1r,3r)-3-cyano-1-(cyanomethyl)cyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)isoxazole-3-carboxylate

A solution of(1r,3r)-3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile(Preparation 75, 110 mg, 0.33 mmol) and ethyl5-(tributylstannyl)isoxazole-3-carboxylate (Preparation 76, 140 mg, 0.33mmol) in 1,4-dioxane (3 mL) was purged with argon for about 5 min,followed by the addition of XPhos Pd G2 (51.2 mg, 0.065 mmol). Themixture was heated at about 100° C. for about 5 hrs. The mixture wasconcentrated and the residue was purified by chromatography to affordthe title compound as a light yellow solid (66 mg, 45%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.44 (s, 1H), 9.02 (s, 1H), 8.60 (s, 1H),8.42 (d, 1H), 7.65 (d, 1H), 7.62 (s, 1H), 4.44 (q, 2H), 3.54-3.63 (m,1H), 3.53 (s, 2H), 3.26-3.36 (m, 2H), 2.90-2.98 (m, 2H), 1.37 (t, 3H).

LCMS m/z=443.3 [MH]⁺

Example 295-(4-(1-((1r,3r)-3-Cyano-1-(cyanomethyl)cyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)isoxazole-3-carboxamide

A solution of ethyl5-(4-(1-((1r,3r)-3-cyano-1-(cyanomethyl)cyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)isoxazole-3-carboxylate(Preparation 77, 54 mg, 0.12 mmol) in methanol (3 mL) was treated with a7 M solution of ammonia gas in methanol (2 mL, 14 mmol). The reactionvessel was tightly sealed and the mixture was heated at about 95° C. forabout 18 hrs. After cooling, the precipitate was filtered, washed withEtOAc followed by Et₂O, and dried to afford the title compound as awhite solid (45 mg, 89%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.36 (s, 1H), 9.01 (s, 1H), 8.58 (s, 1H),8.41 (d, 1H), 8.21 (br. s, 1H), 7.91 (br. s, 1H), 7.64 (d, 1H), 7.50 (s,1H), 3.55-3.62 (m, 1H), 3.53 (s, 2H), 3.26-3.35 (m, 2H), 2.90-2.98 (m,2H).

LCMS m/z=414.3 [MH]⁺

Preparation 782-((1r,3s)-1-(4-(6-(5-(DiBoc)-amino-1-(tetrahydro-2H-pyran-2-yl)-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile

A mixture of3-bromo-1-(tetrahydro-2H-pyran-2-yl)-5-(diBoc)-amino-1H-pyrazole(Preparation 43, 233 mg, 0.52 mmol), KOAc (162 mg, 1.57 mmol), andbis(pinacolato)diboron (199 mg, 0.78 mmol) in 1,4-dioxane (4 mL) waspurged with argon for about 5 min, after which XPhos Pd G2 (82.1 mg,0.10 mmol) was added. The mixture was heated at about 65° C. for about3.5 hrs.

After cooling to about 20° C.,2-((1r,3s)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclo-butyl)aceto-nitrile(Preparation 39, 125 mg, 0.36 mmol), 2 M aq. K₃PO₄ (0.783 mL) and XPhosPd G2 (82.1 mg, 0.10 mmol) were added. The mixture was again purged withargon, then heated at about 80° C. for about 1 hrs. After cooling, themixture was diluted with EtOAc and the phases were separated. Theaqueous phase was extracted twice with EtOAc and the combined EtOAcextracts were concentrated. The residue was purified by chromatographyto afford the title compound as a clear oil (220 mg, 62%).

¹H NMR (400 MHz, CDCl₃) δ: 9.08 (s, 1H), 8.39 (s, 1H), 8.33 (s, 1H),8.09 (d, 1H), 6.97 (d, 1H), 6.90 (s, 1H), 5.26 (dd, 1H), 4.03-4.11 (m,2H), 3.64 (t, 1H), 3.34 (s, 3H), 3.25 (s, 2H), 3.11-3.19 (m, 2H),2.55-2.63 (m, 2H), 2.21 (m, 1H), 1.93 (dd, 1H), 1.59-1.84 (m, 4H), 1.45(s, 18H).

LCMS m/z=674.5 [MH]⁺

Example 302-((1r,3s)-1-(4-(6-(3-Amino-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile

TFA (3 mL) was added to a solution of2-((1r,3s)-1-(4-(6-(5-(diBoc)-amino-1-(tetrahydro-2H-pyran-2-yl)-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile(Preparation 78, 220 mg, 0.33 mmol) in DCM (2 mL) at about 20° C. Afterabout 1 hrs at this temperature, the mixture was concentrated and theresidue was dissolved in DCM and saturated aq. NaHCO₃, ensuring that thepH was basic. The DCM was separated and the aqueous phase was extractedtwice with DCM. The combined DCM extracts were dried (Na₂SO₄),concentrated, and the residue was purified by chromatography followed byHPLC to afford the title compound as a white solid (17 mg, 13%).

¹H NMR (400 MHz, CD₃OD) δ: 8.89 (s, 1H), 8.84 (s, 1H), 8.54 (s, 1H),8.17-8.18 (m, 1H), 7.34 (s, 1H), 6.22 (s, 1H), 4.09-4.12 (m, 1H), 3.39(s, 3H), 3.22-3.27 (m, 2H), 2.56-2.60 (m, 2H).

LCMS m/z=390.3 [MH]⁺

Preparation 79 (4-Bromo-1-methyl-1H-pyrazol-3-yl)methanol

Sodium borohydride (3.4 g, 90 mmol) was added to a solution of ethyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate (4.2 g, 18 mmol) in anhydrousEtOH (150 mL) at about 5° C. The mixture was then heated at about 50° C.for about 16 h, after which EtOAc (100 mL) and water (100 mL) wereadded. The EtOAc was separated, dried (Na₂SO₄), and concentrated. Theresidue was purified by chromatography to afford the title compound as awhite solid (1.05 g, 31%).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.84 (s, 1H), 5.01 (td, 1H), 4.33 (d, 2H),3.77 (s, 3H).

LCMS m/z=192.7 [MH]⁺ (⁸¹Br isotope)

Preparation 804-Bromo-1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole

To a solution of (4-bromo-1-methyl-1H-pyrazol-3-Amethanol (Preparation79, 1.00 mg, 5.23 mmol) in THF (30 mL) were added DHP (1.32 g, 15.7mmol) and PTSA (19.9 mg, 0.10 mmol). The solution was heated at about50° C. for about 16 hrs. The mixture was concentrated and the residuewas purified by chromatography to afford the title compound as acolorless oil (1.02 g, 71%).

¹H NMR (400 MHz, CDCl₃) δ: 7.36 (s, 1H), 4.80 (t, 1H), 4.73 (d, 1H),4.45 (d, 1H), 3.95-4.03 (m, 1H), 3.87 (s, 3H), 3.53-3.64 (m, 1H),1.78-1.93 (m, 1H), 1.60-1.77 (m, 3H), 1.45-1.60 (m, 2H).

LCMS m/z=174.6 [MH-THP]⁺

Preparation 811-Methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a solution of4-bromo-1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazole(Preparation 80, 330 mg, 1.20 mmol) in DMF (12 mL) were addedbis(pinacolato)diboron (457 mg, 1.8 mmol) and KOAc (353 mg, 3.6 mmol).The mixture was purged with nitrogen for about 2 min, after whichPd(dppf)Cl₂ (87.8 mg, 0.12 mmol) was added. The mixture was heated atabout 90° C. for about 16 hrs. The cooled mixture was filtered through apad of Celite® and the filter was washed with methanol (15 mL). Thefiltrate was concentrated to afford the impure title compound as darkgum (1.17 g), which was used in Example 31 next step without furtherpurification.

¹H NMR (400 MHz, CDCl₃) δ: 7.61 (s, 1H), 4.75-4.77 (m, 1H), 4.50-4.57(m, 2H), 4.03-4.10 (m, 1H), 3.91-3.98 (m, 1H), 3.89 (s, 3H), 1.81-1.90(m, 1H), 1.61-1.76 (m, 3H), 1.49-1.56 (m, 2H), 1.30 (s, 12H).

LCMS m/z=239.1 [MH-THP]⁺

Example 312-((1r,3s)-1-(4-(6-(3-(Hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile

Part 1

A mixture of2-((1r,3s)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxy-cyclobutyl)acetonitrile(Preparation 39, 80 mg, 0.23 mmol),1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4, 5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 81, 376mg, 1.17 mmol), and 2 M aq. K₃PO₄ (0.35 mL) in 1,4-dioxane (2.5 mL) wastreated with XPhos Pd G2 (18.4 mg, 0.023 mmol) and the mixture waspurged with nitrogen. The mixture was heated at about 60° C. for about20 hrs. The mixture was concentrated and the residue was purified bychromatography to afford the title compound as a yellow gum. This samplewas combined with the product from an equivalent reaction conductedusing2-((1r,3s)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile(Preparation 39, 120 mg, 0.35 mmol),1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Preparation 81, 564 mg, 1.75 mmol), 2 M aq. K₃PO₄ (0.525 mL), and XPhosPd G2 (13.8 mg, 0.023 mmol) in 1,4-dioxane (3.5 mL) to afford2-((1r,3s)-3-methoxy-1-(4-(6-(1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrilein a total yield of 150 mg (51%), which was used in Part 2 withoutfurther purification.

Part 2

TFA (1 mL) was added to an ice-cooled solution of24(1r,3s)-3-methoxy-1-(4-(6-(1-methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile(Part 1, 150 mg, 0.30 mmol) in DCM (3 mL). The mixture was stirred withcooling in ice for about 2 hrs, then concentrated. The residue waspurified by HPLC to afford the title compound as a light yellow solid(53 mg, 38%).

¹H NMR (400 MHz, CD₃OD) δ: 8.87 (s, 1H), 8.69 (s, 1H), 8.40 (s, 1H),8.21 (s, 1H), 8.13 (d, 1H), 7.28 (d, 1H), 4.83 (s, 2H), 4.05-4.14 (m,1H), 3.96 (s, 3H), 3.37 (s, 2H), 3.34 (s, 3H), 3.18-3.27 (m, 2H),2.53-2.62 (m, 2H).

LCMS m/z=419.1 [MH]⁺

Preparation 822-((1s,3r)-1-(4-(6-Chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile

Part 1

To a solution of2-((1s,3r)-1-(4-bromo-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile(Preparation 37, cis isomer, 400 mg, 1.48 mmol) in toluene (9 mL) wereadded bis(pinacolato)diboron (564 mg, 2.22 mmol) and KOAc (436 mg, 4.44mmol). The mixture was purged with nitrogen for about 3 min, after whichPd(dppf)Cl₂ (108 mg, 0.15 mmol) was added. The mixture was again purgedwith nitrogen for about 3 min, then heated at about 110° C. for about 16hrs. The cooled mixture was concentrated and the residue was purified bychromatography to afford impure 2-((1s,3r)-3-methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile aslight-yellow oil (500 mg), which was used in Part 2.

Part 2

A solution of2-((1s,3r)-3-methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile(Part 1, 470 mg, 1.48 mmol) and 4,6-dichloropyrazolo[1,5-a]pyrazine(Preparation 4, 279 mg, 1.48 mmol), and 2 M aq. K₂CO₃ (2.22 mL) in1,4-dioxane (10 mL) was purged with nitrogen for about 2 min, afterwhich Pd(dppf)Cl₂ (108 mg, 0.15 mmol) was added. The mixture was againpurged with nitrogen for about 3 min, then heated at about 90° C. forabout 16 hrs. The cooled mixture was concentrated and the residue waspurified by chromatography to afford the title compound as a yellowsolid (130 mg, 26%).

¹H NMR (400 MHz, CDCl₃) δ: 8.40 (s, 1H), 8.35 (s, 1H), 8.27 (s, 1H),8.08 (d, 1H), 7.00 (s, 1H), 4.05 (quin, 1H), 3.30 (s, 3H), 3.10 (s, 2H),3.00 (m, 2H), 2.75 (m, 2H).

LCMS m/z=343.2 [MH]⁺ (Cl³⁵ isotope)

Preparation 83 Ethyl5-(4-(1-((1s,3r)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazole-3-carboxylate

A solution of2-((1s,3r)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile(Preparation 82, 120 mg, 0.35 mmol) and ethyl5-(tributylstannyl)-1H-pyrazole-3-carboxylate (Preparation 31, 150 mg,0.35 mmol) in 1,4-dioxane (5 mL) was treated with XPhos Pd G2 (13.8 mg,0.017 mmol) and the mixture was purged with nitrogen for about 2 min.The mixture was heated at about 110° C. for about 2 hrs. The cooledmixture was concentrated and the residue was purified by chromatographyto afford the title compound as a yellow solid (180 mg).

¹H NMR (400 MHz, CDCl₃) δ: 9.05 (br. s., 1H), 8.39 (s, 1H), 8.32 (s,1H), 8.14 (s, 1H), 7.65 (s, 1H), 7.02 (s, 1H), 6.88 (s, 1H), 4.44-4.50(m, 2H), 4.08 (t, 1H), 3.80 (s, 3H), 3.13 (s, 2H), 3.00-3.08 (m, 2H),2.75-2.83 (m, 2H), 1.46 (t, 3H).

LCMS m/z=447.1 [MH]⁺

Example 325-(4-(14(1s,3r)-1-(Cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazole-3-carboxamide

A solution of ethyl5-(4-(1-((1s,3r)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazole-3-carboxylate(Preparation 83, 100 mg, 0.22 mmol) in MeOH (2 mL) was treated with a 4M solution of ammonia gas in methanol (1 mL). The reaction vessel wastightly sealed and the mixture was heated at about 60° C. for about 16hrs. The mixture was concentrated and the residue was purified by HPLCto afford the title compound (23 mg, 25%).

¹H NMR (400 MHz, DMSO-d₆) δ: 13.79 (br. s., 1H), 9.31 (br. s., 1H), 9.00(br. s., 1H), 8.67 (br. s., 1H), 8.28 (d, 1H), 7.56 (br. s., 2H), 7.39(br. s., 1H), 7.25-7.35 (m, 1H), 4.08 (quin, 1H), 3.44 (s, 2H), 3.21 (s,3H), 2.79-2.90 (m, 2H), 2.63-2.73 (m, 3H).

LCMS m/z=440.1 [MNa]⁺

Preparation 84 2-(Tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazole

To a mixture of 1H-1,2,3-triazole (15 g, 220 mmol) in DCM (724 mL) wereadded DHP (21.9 g, 261 mmol) and PTSA (0.374 g, 2.17 mmol). The mixturewas kept at about 25° C. for about 18 hrs, after which NaOH (96 mg, 2.39mmol) was added. The mixture was stirred at about 25° C. for about 1 hrsthen filtered. The filtrate was concentrated and the residue waspurified by chromatography to afford the title compound as a colorlessoil (18 g, 54%).

¹H NMR (400 MHz, CDCl₃) δ: 7.68 (s, 2H), 5.74 (dd, 1H), 4.00-4.08 (m,1H), 3.69-3.81 (m, 1H), 2.36-2.51 (m, 1H), 2.02-2.20 (m, 2H), 1.61-1.81(m, 3H).

Preparation 852-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole

To a solution of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24 g, 129mmol) in pentane (200 mL) were added 4,4′-di-tert-butyl-2,2′-bipyridine(0.315 g, 1.18 mmol) and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer(234 mg, 0.35 mmol). The solution rapidly became a red color and gasevolution was observed. After about 15 min,2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazole (Preparation 84, 18 g,117 mmol) was added. The mixture was stirred at about 25° C. for about 6h. The mixture was concentrated and the residue was purified bychromatography to afford the title compound as a colorless solid (26 g,79%).

¹H NMR (400 MHz, CDCl₃) δ: 7.99 (s, 1H), 5.81 (dd, 1H), 4.07 (d, 1H),3.67-3.78 (m, 1H), 2.41-2.55 (m, 1H), 2.02-2.16 (m, 2H), 1.60-1.80 (m,3H), 1.37 (s, 12H).

LCMS m/z=113.9 [MH-C₂H₂N]⁺

Preparation 86(1r,3r)-3-(Cyanomethyl)-3-(4-(6-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

A mixture of(1r,3r)-3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile(Preparation 75, 300 mg, 0.89 mmol),2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole(Preparation 85, 248 mg, 0.89 mmol), and 2 M aq. K₃PO₄ (1 mL) in1,4-dioxane (4 mL) was purged with argon for about 5 min, after whichXPhos Pd G2 (140 mg, 0.18 mmol) was added. The mixture was heated atabout 50° C. for about 1 hrs, then cooled and diluted with EtOAc. Thephases were separated and the aqueous phase was extracted twice withDCM. The combined EtOAc and DCM extracts were dried (Na₂SO₄) andconcentrated. The residue was purified by chromatography to afford thetitle compound as a clear gum (384 mg, 95%).

¹H NMR (400 MHz, CDCl₃) δ: 9.02 (s, 1H), 8.41 (s, 1H), 8.35 (s, 1H),8.28 (s, 1H), 8.13 (d, 1H), 7.00 (d, 1H), 5.81 (dd, 1H), 4.06-4.12 (m,1H), 3.77-3.87 (m, 1H), 3.35-3.47 (m, 3H), 3.30 (s, 2H), 2.95-3.04 (m,2H), 2.45-2.59 (m, 1H), 2.12-2.24 (m, 2H), 1.69-1.87 (m, 3H)

LCMS m/z=455.3 [MH]⁺

Preparation 87(1r,3r)-3-(4-(6-(2H-1,2,3-Triazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile

A suspension of(1r,3r)-3-(cyanomethyl)-3-(4-(6-(2-(tetrahydro-2H-pyran-2-yl)-2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(Preparation 86, 384 mg, 0.84 mmol) in MeOH (5 mL) was treated with PTSA(16.1 mg, 0.084 mmol). The mixture was heated at about 60° C. for about3.5 h. The solids dissolved to form a homogeneous solution, after whicha white solid precipitated. Heating was continued for about 1 hrsfurther. The mixture was cooled to about 0° C. for about 30 min andfiltered. The precipitate was washed with MeOH and dried under vacuum toafford the title compound as a white solid (204 mg, 65%).

¹H NMR (400 MHz, DMSO-d₆) δ: 9.05 (s, 1H), 8.97 (s, 1H), 8.72 (br. s.,1H), 8.57 (s, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 7.56 (s, 1H), 3.55-3.62(m, 1H), 3.53 (s, 2H), 3.22-3.30 (m, 2H), 2.89-3.00 (m, 2H).

LCMS m/z=371.3 [MH]⁺

Example 33(1r,3r)-3-(Cyanomethyl)-3-(4-(6-(1-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

To a mixture of(1r,3r)-3-(4-(6-(2H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile(Preparation 87, 100 mg, 0.27 mmol) and K₂CO₃ (75 mg, 0.54 mmol) in DMF(1 mL) was added iodomethane (0.034 mL, 0.540 mmol). The mixture wasstirred for about 2 hrs at about 25° C. The mixture was filtered and thefilter cake was washed twice with DCM. The filtrate was concentrated andthe residue was purified by chromatography followed by HPLC to affordthe title compound as a white solid (40 mg, 39%).

¹H NMR (400 MHz, CDCl₃) δ: 9.19 (s, 1H), 8.51 (s, 1H), 8.33 (s, 1H),8.30 (s, 1H), 8.15 (d, 1H), 7.03 (s, 1H), 4.22 (s, 3H), 3.35-3.46 (m,3H), 3.30 (s, 2H), 2.99 (d, 2H).

LCMS m/z=385.4 [MH]⁺

Example 34(1s,3s)-3-(Cyanomethyl)-1-methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

and

Example 35(1r,3r)-3-(Cyanomethyl)-1-methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

DBU (327 mg, 2.15 mmol) was added to a solution of6-(1-methyl-1H-pyrazol-4-yl)-4-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(Preparation 53, 190 mg, 0.72 mmol) and3-(cyanomethylene)-1-methylcyclobutane-1-carbonitrile (Preparation 89,142 mg, 1.07 mmol) in MeCN (15 mL) and the mixture was stirred at about50° C. for about 4 hrs. The mixture was concentrated and the residue waspurified by chromatography to afford a residue which was furtherpurified by TLC to afford a mixture of the two title compounds (200 mg,70%) as a brown solid. The mixture of isomers was separated by HPLC toafford(1r,3r)-3-(cyanomethyl)-1-methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrileas a light pink solid (trans isomer, 24 mg 8%)

¹H NMR (400 MHz, CD₃CN) δ: 8.36 (s, 1H), 8.28 (s, 1H), 8.26-8.31 (m,1H), 8.14 (s, 1H), 7.86 (s, 1H), 7.79 (d, 1H), 7.73 (s, 1H), 6.87 (d,1H), 3.66 (s, 3H), 3.10 (s, 2H), 2.80-2.92 (m, 4H), 1.25 (s, 3H).

LCMS m/z=398.0 [MH]⁺ and 420.0 [MNa]⁺

and (1s,3s)-3-(cyanomethyl)-1-methyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(cis isomer, 24 mg, 8%).

¹H NMR (400 MHz, CD₃CN) δ: 8.68 (s, 1H), 8.63 (s, 1H), 8.44 (s, 1H),8.14 (s, 1H), 8.05 (d, 1H), 8.00 (s, 1H), 7.15 (d, 1H), 3.92 (s, 3H),3.47-3.55 (m, 2H), 3.19 (s, 2H), 2.74-2.82 (m, 2H), 1.63 (s, 3H).

LCMS m/z=398.0 [MH]⁺ and 419.9 [MNa]⁺

Preparation 88 1-Methyl-3-oxocyclobutane-1-carbonitrile

Part 1

To a solution of diisopropylamine (1.30 g, 12.9 mmol) in THF (30 mL) wasadded 2.5 M n-BuLi (5.15 mL) at about 0° C. The solution was stirred forabout 30 min at about 0° C. before being cooled to about −78° C.3-Methylenecyclobutane-1-carbonitrile (1.00 g, 10.74 mmol) was added andthe solution was stirred for about 1 h at about −78° C. Iodomethane(1.98 g, 14.0 mmol) was added to the solution at about −78° C., then themixture was allowed to warm to about 20° C. and was kept at thistemperature for about 0.5 hrs. Saturated aq. NH₄Cl (30 mL) was added andthe mixture was extracted with EtOAc (3×30 mL). The combined EtOAcextracts were concentrated to afford1-methyl-3-methylenecyclobutane-1-carbonitrile as a pale yellow oil (1.1g, 96%).

¹H NMR (400 MHz, CDCl₃) δ: 4.90-4.98 (m, 2H), 3.23-3.35 (m, 2H),2.64-2.75 (m, 2H), 1.55 (s, 3H).

Part 2

To a mixture of 1-methyl-3-methylenecyclobutane-1-carbonitrile (1.10 g,10.3 mmol) and RuCl₃ hydrate (50.9 mg, 0.23 mmol) in a mixture of DCM(20 mL), MeCN (20 mL) and water (40 mL) was added NaIO₄ (8.78 g, 41.1mmol) in small portions at about 5° C. The mixture was then stirred atabout 25° C. for about 17 hrs. The aqueous phase was separated andextracted with DCM (2×50 mL). The DCM extracts were combined with theDCM-MeCN phase and dried (Na₂SO₄), then filtered through about 10 g ofsilica gel. The silica gel was washed with DCM (50 mL). The filtrate wasconcentrated to afford the title compound as a brown oil (0.80 g, 71%).

¹H NMR (400 MHz, CDCl₃) δ: 3.71 (m, 2H), 3.14 (m, 2H), 1.71 (s, 3H).

Preparation 89 3-(Cyanomethylene)-1-methylcyclobutane-1-carbonitrile

A mixture of 1-methyl-3-oxocyclobutane-1-carbonitrile (Preparation 88,0.80 g, 7.0 mmol), (EtO)₂P(O)CH₂CN (1.43 g, 8.06 mmol), LiBr (0.955 g,11.0 mmol) and TEA (1.48 g, 14.7 mmol) in THF (20 mL) was stirred atabout 25° C. for about 16 hrs. Water (30 mL) was added and the mixturewas extracted with EtOAc (3×50 mL). The combined EtOAc extracts weredried (Na₂SO₄) and concentrated. The residue was purified bychromatography to afford the title compound as a colorless oil (0.65 g,70%).

¹H NMR (400 MHz, CDCl₃) δ: 5.34 (m, 1H), 3.47 (m, 2H), 2.98 (m, 2H),1.60 (s, 3H). GCMS m/z=131 [M−H]⁺

Preparation 90 2-(3-Methoxycyclobutylidene)acetonitrile

Part 1

Twelve Identical reactions were carried out in parallel as follows:

For each reaction, a 100 mL sealed tube was charged with methoxyethene(37 g, 637 mmol), DIPEA (9.88 g, 76.4 mmol), and acetyl chloride (5 g,60 mmol) at about −30° C. The mixture was then heated at about 70° C.for about 5 hrs. The twelve reactions were combined and washed with 1 Maq. HCl (2×100 mL), saturated aq. NaHCO₃ (2×100 mL), dried (Na₂SO₄) andconcentrated to afford a crude specimen of 3-methoxycyclobutan-1-one asa black oil (27 g, 37%). This material was about 50% pure as judged by¹H NMR and was used without further purification in Part 2.

Part 2

Two identical reactions were carried out in parallel.

To a mixture of LiBr (13.4 g, 154 mmol) and TEA (39 mL, 280 mmol) in THF(200 mL) was added (EtO)₂P(O)CH₂CN (26 g, 147 mmol) at about 0° C.Stirring was continued at about 25° C. for about 2 hrs. To this mixturewas added a solution of the crude 3-methoxycyclobutan-1-one prepared inPart 1 (13 g, about 70 mmol) in THF (40 mL) at about 0° C. The mixturewas then stirred at about 25° C. for about 16 hrs. The two reactionmixtures were combined and concentrated. The residue was purified bychromatography to afford the title compound as a light yellow oil (9.2g, 56%).

¹H NMR (400 MHz, CDCl₃) δ: 5.25 (m, 1H), 4.05 (m, 1H), 3.30 (s, 3H),3.25 (m, 1H), 3.10 (m, 1H), 2.85 (m, 2H).

LCMS m/z=124.08 [MH]⁺

Preparation 91(1r,3r)-3-(Cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(trans isomer)

and

(1s,35)-3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(cis isomer)

To a solution of4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.3 kg,6.67 mol) in MeCN (43 L) were added3-cyanomethylene)cyclobutane-1-carbonitrile (Preparation 27, 953 g, 8mol) and DBU (3.06 kg, 20.1 mol) at about 20° C. Stirring was continuedat about 20° C. for about 16 hrs. The mixture was poured into 1 M aq.KH₂PO4 (10 L) and extracted with EtOAc (5×5 L). The combined EtOAcextracts were concentrated and the residue was purified bychromatography to afford(1r,3r)-3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrileas a white solid (trans isomer, 610 g, 30%) melting point 137-140° C.

¹H NMR (400 MHz, CDCl₃) δ: 7.90 (s, 1H), 7.88 (s, 1H), 3.21-3.28 (m,3H), 3.19 (s, 2H), 2.86-2.94 (m, 2H), 1.33 (s, 12H).

¹³C NMR (101 MHz, CD₃OD) δ: 147.54, 136.49, 122.49, 117.11, 84.96,61.93, 37.52, 30.47, 25.28, 25.18, 17.21.

LCMS m/z=313.1 [MH]⁺

and (1s, 3s)-3-(cyanomethyl)-3-(4-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile as anoff-white solid (cis isomer, 250 g, 12%).

melting point 95-98° C.

¹H NMR (400 MHz, CDCl₃) δ: 7.86 (s, 2H), 3.24-3.31 (m, 1H), 3.13-3.21(m, 2H), 3.07 (s, 2H), 2.96-3.04 (m, 2H), 1.34 (s, 12H).

¹³C NMR (101 MHz, CD₃OD) δ: 147.43, 135.94, 121.94, 117.37, 84.98,75.96, 60.10, 37.95, 28.42, 25.29, 16.16.

LCMS m/z=313.1 [MH]⁺

Preparation 92 5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

and

3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A mixture of 3-methylpyrazole (1.00 g, 12.18 mmol), DHP (1.54 g, 18.3mmol) and TFA (0.007 mL, 0.089 mmol) was heated at about 85° C. forabout 4 hrs. The mixture was cooled to about 20° C. and NaH (60% in oil,20 mg, 0.5 mmol) was added. Stirring at about 20° C. was continued forabout 18 hrs. The mixture was concentrated the residue was purified bychromatography to afford5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole as an oil (400 mg,20%)

¹H NMR (400 MHz, CDCl₃) δ: 7.45 (d, 1H), 6.05 (d, 1H), 5.24-5.30 (m,1H), 4.00-4.08 (m, 1H), 3.61-3.70 (m, 1H), 2.41-2.55 (m, 1H), 2.35 (s,3H), 2.08-2.18 (m, 1H), 1.93-2.02 (m, 1H), 1.65-1.77 (m, 2H), 1.55-1.64(m, 1H).

GCMS m/z=166.1 [M]⁺

and 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole as an oil (352 mg,15%).

¹H NMR (400 MHz, CDCl₃) δ: 7.48 (d, 1H), 6.08 (d, 1H), 5.29 (dd, 1H),4.08 (dt, 1H), 3.64-3.74 (m, 1H), 2.30 (s, 3H), 2.07-2.18 (m, 1H),1.98-2.07 (m, 2H), 1.64-1.77 (m, 3H).

GCMS m/z=166.1 [M]⁺

Preparation 933-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A 2.5 M solution of n-BuLi in hexane (0.44 mL, 1.10 mmol) was added to asolution of 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(Preparation 92, 200 mg, 1.10 mmol) in THF (2 mL) at about −70° C. Themixture was stirred at this temperature for about 10 min before2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (214 mg, 1.15 mmol)was added. The mixture was kept at about −70° C. for about 1 hrs longer,then warmed to about 20° C. and concentrated to afford the titlecompound admixed with about 65% unreacted3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole. This mixture was usedwithout further purification.

¹H NMR (400 MHz, CDCl₃) δ: 6.51 (s, 1H), 5.76 (dd, 1H), 4.01-4.12 (m,1H), 3.59-3.74 (m, 1H), 2.37-2.51 (m, 2H), 2.29 (s, 3H), 1.97-2.18 (m,1H), 1.62-1.76 (m, 2H), 1.47-1.62 (m, 1H), 1.33 (s, 12H).

GCMS m/z=292.2 [M]⁺

Preparation 94 3-(Benzyloxy)-N-methoxy-N-methylcyclobutanecarboxamide

To a solution of 3-(benzyloxy)cyclobutanecarboxylic acid (324 g, 1.57mol) in DCM (1.5 L) was added CDI (280 g, 1.73 mol) in portions. Themixture was heated at reflux for about 2 hrs, after whichN,O-dimethylhydroxylamine hydrochloride (183.7 g, 1.88 mol) and TEA (261mL, 1.88 mol) were added. The mixture was heated at reflux for about 3hrs further, then stirred at about 25° C. for about 16 hrs. The DCM waswashed with saturated aq. K₂CO₃, dried (K₂CO₃), and concentrated. Theresidue was purified by chromatography to afford the title compound (298g, 76%).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.24-7.38 (m, 5H), 4.37 (s, 2H), 4.06-4.15(m, 1H), 3.61 (s, 3H), 3.09 (s, 3H), 2.96 (s, 1H), 2.30-2.40 (m, 2H),2.09-2.22 (m, 1H), 1.95-2.07 (m, 1H).

Preparation 95 1-[3-(Benzyloxy)cyclobutyl]ethanone

To a solution of 3-(benzyloxy)-N-methoxy-N-methylcyclobutanecarboxamide(Preparation 94, 298 g, 1.2 mol) in THF (1.5 L) was added dropwise asolution of methylmagnesium bromide (1.3 mol) at about 20° C. After theaddition of methylmagnesium bromide was completed, the cooling bath wasremoved and the mixture was allowed to warm to about 25° C. Then 0.5 Maq. HCl (2.5 L) was added, and the mixture was extracted with Et₂O (1L+500 mL). The combined Et₂O extracts were washed with water, dried(Na₂SO₄), and concentrated. The residue was purified by chromatographyto afford the title compound (194 g, 79%).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.24-7.38 (m, 5H), 4.35 (s, 2H), 3.90-3.99(m, 0.5H), 3.16-3.24 (m, 0.5H), 2.75-2.87 (m, 1H), 2.31-2.40 (m, 2H),2.06-2.15 (m, 1H), 2.04 (s, 1.5H), 1.99 (s, 1.5H), 1.87-1.97 (m, 1H).

Preparation 961-[3-(Benzyloxy)cyclobutyl]-3-(dimethylamino)prop-2-en-1-one

To a solution of 1-[3-(benzyloxy)cyclobutyl]ethanone (Preparation 95,194g, 0.95 mol) in DMF (500 mL) was added dimethylformamide dimethyl acetal(285 g, 2.4 mol). The mixture was heated at about 110° C. for about 12hrs. The mixture was concentrated to afford the title compound (258 g),which was used without purification or further characterization.

Preparation 97 5-[3-(Benzyloxy)cyclobutyl]-1H-pyrazole

To a solution of1-[3-(benzyloxy)cyclobutyl]-3-(dimethylamino)prop-2-en-1-one(Preparation 96, 110 g, 0.42 mol) in MeOH (500 mL) was added hydrazinehydrate (30 g, 0.6 mol). The mixture was heated at reflux for about 12hrs, then concentrated. The residue was purified by chromatography toafford the title compound (79 g, 82%), which was used withoutpurification or further characterization.

Preparation 98 3-(1H-Pyrazol-5-yl)cyclobutanol

To a solution of 5-[3-(benzyloxy)cyclobutyl]-1H-pyrazole (Preparation97, 79 g, 0.35 mol) in methanol (800 mL) in a 2 L hydrogenation flaskwas added palladium on carbon (10% Pd, 16 g). The mixture waspressurized under hydrogen (30 psi) and the mixture was shaken at about60° C. for about 12 hrs. Additional palladium on carbon (10% Pd, 16 g)was added, and the hydrogenation was continued for about 10 hrs. Themixture was filtered and the filtrate was concentrated. The residue waspurified by chromatography to afford the title compound (46 g, 96%),which was used without purification or further characterization.

Preparation 99 3-(1H-pyrazol-5-yl)cyclobutane-1-one

To a solution of oxalyl chloride (7.8 mL, 0.09 mol) in DCM (50 mL) atabout −78° C. was added dropwise a solution of DMSO (12.7 mL, 0.18 mol)in DCM (50 mL). The mixture was stirred for about 30 min, then3-(1H-pyrazol-5-yl)cyclobutanol (Preparation 98, 13.7 g, 0.09 mol) wasadded dropwise at this temperature. The resulting mixture was kept forabout 30 min, after which TEA (25 mL, 0.18 mol) was added dropwise. Thecooling bath was removed and the mixture was allowed to warm to about25° C. and was kept at that temperature for about 3 hrs. Then an aqueoussolution of K₂CO₃ (100 mL) was added. The DCM was separated, and theaqueous phase was extracted with DCM. The combined DCM extracts werewashed with water, dried (Na₂SO₄), and concentrated. The residue waspurified by chromatography to afford the title compound (7.4 g, 55%) asa white solid.

¹H NMR (400 MHz, DMSO-d₆) δ: 12.56 (s, 1H), 7.61 (s, 1H), 6.21 (d, 1H),3.46-3.68 (m, 1H), 3.37-3.46 (m, 2H), 3.15-3.25 (m, 2H).

LCMS m/z=137.1 [MH]⁺

Preparation 1002-((1r,3s)-1-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile(trans isomer)

Part 1

To a solution of2-((1r,3s)-1-(4-bromo-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile(Preparation 37, trans isomer, 3399 mg, 12.58 mmol) in 1,4-dioxane (33mL) were added bis(pinacolato)diboron (3510 mg, 13.8 mmol) and KOAc(3700 mg, 37.7 mmol). The mixture was purged with argon for about 5 min,after which XPhos Pd G2 (1980 mg, 2.52 mmol) was added. The mixture washeated at about 65° C. for about 4 hrs. The cooled mixture wasconcentrated and the residue was purified by chromatography. The productwas stirred with EtOAc (10 mL) at about 25° C., then heptane (40 mL) wasadded and crystallization was allowed to occur for about 30 min. Theprecipitate was filtered and dried to afford2-((1r,3s)-3-methoxy-1-(4-(4,4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile as awhite solid (1950 mg, 49%).

¹H NMR (400 MHz, CDCl₃) δ: 7.91 (s, 1H), 7.87 (s, 1H), 3.98 (tt, 1H),3.29 (s, 3H), 3.17 (s, 2H), 2.97-3.07 (m, 2H), 2.44-2.53 (m, 2H), 1.33(s, 12H).

LCMS m/z=318.0 [MH]⁺

Part 2

A solution of 2-((1r, 35)-3-methoxy-1-(4-(4,4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutyl)acetonitrile (Part 1,1950 mg, 6.15 mmol) and 4,6-dichloropyrazolo[1,5-a]pyrazine (Preparation4, 1160 mg, 6.15 mmol), and 2 M aq. K₃PO₄ (9.22 mL) in 1,4-dioxane (25mL) was purged with argon for about 5 min, after whichbis(tri-t-butylphosphine)palladium(0) (157 mg, 0.31 mmol) was added. Themixture was stirred at about 25° C. for about 2 hrs. The cooled mixturewas diluted with EtOAc and the phases were separated. The aqueous phasewas extracted twice with DCM. The combined EtOAc and DCM extracts weredried (Na₂SO₄) and concentrated. The residue was dissolved in DCM (20mL) and heated at about 40° C. until all was dissolved, then heptane (10mL) was added and crystallization was allowed to occur for about 30 min.The precipitate was filtered and dried to afford the title compound asan off white solid (1120 mg, 53%). The filtrate was concentrated and theresidue was purified by chromatography to afford additional titlecompound (640 mg, 30%).

¹H NMR (500 MHz, CDCl₃) δ: 8.39 (d, 1H), 8.38 (s, 1H), 8.28 (s, 1H),8.08 (d, 1H), 7.03 (dd, 1H), 4.03-4.10 (m, 1H), 3.34 (s, 3H), 3.25 (s,2H), 3.08-3.16 (m, 2H), 2.53-2.60 (m, 2H).

LCMS m/z=343.3 [MH]⁺ (Cl³⁵ isotope)

Preparation 101 Ethyl5-methyl-1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3-carboxylate

Ethyl 3-methyl-1H-pyrazole-5-carboxylate (92 mg, 0.6 mmol),2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one (Preparation 6, 134 mg,0.66 mmol) and K₂CO₃ (104 mg, 0.75 mmol). were combined in MeCN (2 mL)and the suspension was stirred at about 40° C. for about 16 hrs. Thesolids were filtered and the filtrate was concentrated. The residue waspurified by chromatography to afford the title compound as a yellow oil(125 mg, 5.5%).

¹H NMR (400 MHz, CDCl₃) δ: 7.86 (s, 2H), 6.73 (s, 1H), 5.65 (s, 2H),4.26 (q, 2H), 3.95 (s, 3H), 2.32 (s, 3H), 1.31 (t, 3H).

LCMS m/z=277.1 [MH]⁺

Preparation 1022-Methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol

To a solution of ethyl5-methyl-1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3-carboxylate(Preparation 101, 125 mg, 0.45 mmol) in EtOH (5 mL) was added NH₄OAc(105 mg, 1.06 mmol). The mixture was heated under microwave irradiationat about 105° C. for about 4 hrs. The mixture was concentrated and theresidue was dissolved in EtOH and concentrated again to afford the titlecompound (110 mg, 85%).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.25 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H),6.76 (s, 1H), 3.87 (s, 3H), 2.34 (s, 3H).

LCMS m/z=230.0 [MH]⁺

Preparation 1034-Chloro-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine

2-Methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol(Preparation 102) was suspended in POCl₃ and heated at about 120° C. forabout 6 hrs. The solution was concentrated afford an impure sample ofthe title compound which was used in the next step without furtherpurification.

LCMS m/z=248.0 [MH]⁺ (Cl³⁵ isotope)

Example 36(1r,3r)-3-(Cyanomethyl)-3-(4-(2-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(trans isomer)

A mixture of crude4-chloro-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine(Preparation 103, 100 mg, 0.40 mmol),(1r,3r)-3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(Preparation 91, 132 mg, 0.42 mmol), Pd(dppf)Cl₂ DCM (16.5 mg, 0.02mmol), and K₂CO₃ (167 mg, 1.21 mmol) were combined in a mixture of1,4-dioxane (2.5 mL) and water (0.5 mL). The mixture was purged withnitrogen for about 5 min, then heated at about 90° C. for about 3 hrs.The mixture was concentrated and the residue was purified bychromatography and HPLC to afford the title compound (5.6 mg, 3% overtwo steps).

¹H NMR (400 MHz, CDCl₃) δ: 8.37 (s, 1H), 8.33 (s, 1H), 8.30 (s, 1H),7.92 (s, 1H), 7.90 (s, 1H), 6.68 (s, 1H), 3.99 (s, 3H), 3.32-3.42 (m,3H), 3.27 (s, 2H), 2.93-3.02 (m, 2H), 2.56 (s, 3H)

LCMS m/z=398.0 [MH]⁺

Preparation 104 3-((4-Methoxybenzyl)oxy)-1-methyl-1H-pyrazole

To a 100 mL round bottom flask were added 1-methyl-1H-pyrazol-3-ol (1.40g, 14.3 mmol), DMF (30 mL), and K₂CO₃ (3.94 g, 28.5 mmol). Lastly4-methoxybenzyl chloride (2.32 mL, 17.1 mmol) was added to the mixture.The mixture was heated at about 60° C. for about 8 hours. The mixturewas then diluted with water (80 mL) and extracted with EtOAc (60 mL×3).The combined EtOAc extracts were washed with brine (60 mL×2), dried(Na₂SO₄) and concentrated. The residue was purified by chromatography toafford the title compound as a colorless oil (2.6 g, 83%).

¹H NMR (400 MHz, CDCl₃) δ: 7.38 (d, 2H), 7.13 (d, 1H), 6.91 (d, 2H),5.64 (d, 1H), 5.11 (s, 2H), 3.82 (s, 3H), 3.76 (s, 3H).

LCMS m/z=218.9 [MH]⁺

Preparation 105 4-Iodo-34(4-methoxybenzyl)oxy)-1-methyl-1H-pyrazole

To a 100 mL round bottom flask were added3-((4-methoxybenzyl)oxy)-1-methyl-1H-pyrazole (Preparation 104, 1.0 g,4.58 mmol) and MeCN (20 mL), after which ceric ammonium nitrate (1.51 g,2.75 mmol) and iodine (698 mg, 2.75 mmol) were added to the mixture. Thebrown mixture was stirred at about 20° C. for about 1 h. The mixture wasquenched with 5% aqueous sodium bisulfite (50 mL) and extracted withEtOAc (40 mL×3). The combined EtOAc extracts were dried (Na₂SO₄) andconcentrated. The residue was purified by chromatography to afford thetitle compound as a green oil (800 mg, 51%).

¹H NMR (400 MHz, CDCl₃) δ: 7.40 (d, 2H), 7.19 (s, 1H), 6.91 (d, 2H),5.18 (s, 2H), 3.82 (s, 3H), 3.77 (s, 3H).

Preparation 1063-((4-Methoxybenzyl)oxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a 100 mL round bottom flask were added4-iodo-3-((4-methoxybenzyl)oxy)-1-methyl-1H-pyrazole (Preparation 105,800 mg, 2.32 mmol) and THF (16 mL). followed by the dropwise addition ofisopropylmagnesium chloride (1.3 M in THF, 2.15 mL, 2.79 mmol) to themixture at about −10° C. The mixture was stirred at a temperaturebetween about −18° C. and 10° C. for about 45 min.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (649 mg, 3.49 mmol)was added to the mixture at about −10° C. and the mixture was allowed towarm to about 15° C. for about 1.5 h. Additional isopropylmagnesiumchloride (1.3 M in THF, 0.72 mL, 0.93 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (216 mg, 1.16 mmol)were added to the mixture at about −15° C. The mixture was allowed towarm to about 15° C. for about 1 h. The mixture was diluted with EtOAc(40 mL) and washed with saturated aqueous NH₄Cl (30 mL), brine (30 mL),dried (Na₂SO₄), and concentrated. The residue was purified bychromatography to afford the title compound as a white solid (600 mg,75%).

¹H NMR (400 MHz, CDCl₃) δ: 7.40-7.45 (m, 3H), 6.88 (d, 2H), 5.24 (s,2H), 3.81 (s, 3H), 3.73 (s, 3H), 1.31 (s, 12H).

LCMS m/z=345.1 [MH]⁺

Preparation 107(1r,3r)-3-(Cyanomethyl)-3-(4-(6-(34(4-methoxybenzyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

To a 25 ml round bottom flask were added(1r,3r)-3-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile(Preparation 75, 300 mg, 0.88 mmol),3-((4-methoxybenzyl)oxy)-1-methyl-4-(4,4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation 106, 367 mg, 1.07 mmol),dioxane (16 mL), XPhos Pd G2 (140 mg, 0.178 mmol) and 2 M aq. K₃PO₄(3.55 mL, 7.11 mmol). The mixture was placed under nitrogen, then heatedat about 60° C. for about 4 h. The mixture was diluted with water (70mL) and extracted with EtOAc (50 mL×3). The combined EtOAc extracts weredried (Na₂SO₄) and concentrated. The residue was purified bychromatography to afford the title compound as a yellow solid (450 mg,98%).

¹H NMR (400 MHz, DMSO-d₆) δ: 8.92 (s, 1H), 8.57 (s, 1H), 8.52 (s, 1H),8.31 (s, 1H), 8.16 (d, 1H), 7.50 (d, 2H), 7.45 (s, 1H), 7.00 (d, 2H),5.29 (s, 2H), 3.95 (s, 3H), 3.82 (s, 3H), 3.55-3.59 (m, 1H), 3.52 (s,2H), 3.25-3.32 (m, 2H), 2.94 (dd, 2H).

LCMS m/z=542.1 [MNa]⁺

Example 37(1r,3r)-3-(Cyanomethyl)-3-(4-(6-(1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(trans isomer)

(1r,3r)-3-(Cyanomethyl)-3-(4-(6-(34(4-methoxybenzyl)oxy)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(Preparation 107, 450 mg, 0.86 mmol) and TFA (13 mL) were stirred atabout 10° C. for about 4 h. The mixture was concentrated and the residuewas diluted with DCM (40 mL) and MeOH (40 mL) and neutralized with solidNaHCO3. The mixture was filtered. The filtrate was concentrated and theresidue was purified by HPLC to afford the title compound as a yellowsolid (54 mg, 16%).

¹H NMR (400 MHz, DMSO-d₆) δ: 10.76 (br. s., 1H), 8.92 (s, 1H), 8.71 (s,1H), 8.51 (s, 1H), 8.18 (d, 1H), 8.16 (s, 1H), 7.45 (d, 1H), 3.73 (s,3H), 3.55-3.62 (m, 1H), 3.53 (s, 2H), 3.25-3.33 (m, 2H), 2.90-2.99 (m,2H).

LCMS m/z=400.1 [MH]⁺

Biological Evaluation

Compounds of the invention were evaluated by in vitro methods todetermine their respective ability to inhibit the JAK kinases (TYK2,JAK1, JAK2, JAK3).

Assay Format

The human JAK inhibitory activity was determined by using a microfluidicassay to monitor phosphorylation of a synthetic peptide by therecombinant human kinase domain of each of the four members of the JAKfamily, JAK1, JAK2, JAK3 and TYK2. Reaction mixtures contained 1 μM of afluorescently labeled synthetic peptide, a concentration less than theapparent K_(m), and 1 mM ATP. Each assay condition was optimized forenzyme concentration and room temperature incubation time to obtain aconversion rate of 20% to 30% phosphorylated peptide product. Reactionswere terminated by the addition of stop buffer containing EDTA.Utilizing the LabChip 3000 mobility shift technology (Caliper LifeScience), each assay reaction was sampled to determine the level ofphosphorylation. This technology is separation-based, allowing directdetection of fluorescently labeled substrates and products. Separationsare controlled by a combination of vacuum pressure and electric fieldstrength optimized for each peptide substrate.

Assay Protocol JAK Caliper Enzyme Assay at 1 mM ATP

Compounds were added to a 384-well plate. Reaction mixtures contained 10mM HEPES, pH 7.4, 10 mM MgCl₂, 0.01% BSA, 0.0005% Tween 20, 1 mM ATP and1 μM peptide substrate. The JAK1 and TYK2 assays contained 1 μM of theIRStide peptide (5FAM-KKSRGDYMTMQID) and the JAK2 and JAK3 assayscontained 1 μM of the JAKtide peptide (FITC-KGGEEEEYFELVKK). The assayswere initiated by the addition of 20 nM JAK1, 1 nM JAK2, 1 nM JAK or 1nM TYK2 enzyme and were incubated at room temperature for three hoursfor JAK1, 60 minutes for JAK2, 75 minutes for JAK3 or 135 minutes forTYK2. Enzyme concentrations and incubation times were optimized for eachnew enzyme preps and were modified slightly over time to ensure 20% to30% phosphorylation. The assays were stopped with 15 μL of 180 mM HEPES,pH 7.4, 20 mM EDTA, and 0.2% Coating Reagent 3. The assay plates wereplaced on a Caliper Life Science LC3000 instrument, and each well wassampled using appropriate separation conditions to measure theunphosphorylated and phosphorylated peptide.

Data Analysis

The data was collected using the HTS Well Analyzer software from CaliperLife Sciences. The data output for data analysis is the percent productconverted calculated on peak height (Equation 1).

% product converted=100*((product)/(product+substrate))  Equation 1:

The percent effect at each compound concentration was calculated basedon the positive and negative control well contained within each assayplate (Equation 2). The positive control wells contained a saturatingconcentration of a control compound that produced a level ofphosphorylation comparable to background (i.e., completely inhibitedJAK1, JAK2, JAK3 or TYK2). The negative control wells contained DMSOalone (at the same concentration as the compound wells) that was used toset the baseline activity in the assay (i.e., uninhibited JAK1, JAK2,JAK3 or TYK2).

% effect=100*((sample well−negative control)/(positive control-negativecontrol))  Equation 2:

The percent effect was plotted against the compound concentrationcompound. An unconstrained sigmoid curve was fitted using a 4 parameterlogistic model and the compound concentration required for 50%inhibition (IC₅₀) was determined (Equation 3).

y=((max−min)/(1+((x/IC ₅₀)̂s)))+min  Equation 3:

Where max is the maximum asymptote (complete inhibition), min is theminimum asymptote (no inhibition) and s is the slope factor. IC₅₀ valuesare reported in nM for each compound:

TABLE I JAK Caliper Data TYK2 JAK1 JAK2 JAK3 Example IC50 IC50 IC50 IC50No. (nM) (nM) (nM) (nM) 1 18 291 40 >9788 2 62 1057 299 >10000 3 64 2292487 >10000 4 55 1338 141 >10000 5 35 1917 472 >10000 6 21 5720500 >10000 7 7 250 37 6682 8 11 265 42 >9282 9 8 185 49 >10000 10 5805709 1601 >10000 11 8 273 38 >6170 12 24 764 159 >10000 13 149 3228487 >10000 14 81 1061 367 >10000 15 22 1495 228 >9121 16 16 664 99 1000017 35 1728 205 10000 18 47 1079 206 10000 19 6 21 8 1051 20 16 38374 >10000 21 34 1288 109 >10000 22 30 2544 127 >10000 23 9 431 26 941024 25 3550 432 >10000 25 23 319 99 >10000 26 21 713 158 >10000 27 24 737171 >10000 28 27 1362 249 >10000 29 352 3932 3041 >10000 30 7 17471 >10000 31 38 >9857 324 >10000 32 17 2254 339 >10000 33 52 8717444 >10000 34 11 96 19 3263 35 136 1915 268 >10000 36 1605 3521755 >10000 37 32 3489 166 >10000Selected compounds were assessed for their ability to inhibit IL-12signaling in a human whole blood flow cytometry assay. IL-12 signalsthrough TYK2 and JAK2.

Human Whole Blood IL-12 Induced STAT4 Phosphorylation Assay

Test articles were prepared as 30 mM stocks in DMSO. An 11-point 2.5dilution series was created in DMSO with a top concentration of 10 mM.Further dilution was done by adding 4 μL of the above test articlesolutions into 96 μL of PBS with a top concentration of 400 μM. Humanwhole blood was collected from healthy donors via vein puncture intoVacutainer collection tubes containing sodium heparin (Catalog No.366480; Becton Dickinson, Franklin Lakes, N.J.). Blood was warmed to 37°C. prior to use. Human whole blood was aliquoted (90 mL/well) in96-well, deep-well, V-bottom plates and treated with compounds at 11different concentrations (0.2% DMSO final) at 37° C. for 60 minutes.This was followed by a challenge with IL-12 (5 mL/well; final, 5 ng/mL)for 15 minutes. Samples were treated with warm 1× Lyse/Fix buffer (700mL/well) to terminate activation and further incubated at 37° C. for 20minutes to lyse red blood cells. Plates were centrifuged at 300×g for 5minutes, supernatant was aspirated, and cells were washed with 800 mLper well of staining buffer (PBS containing 0.5% fetal bovine serum and0.01% sodium azide). The washed cell pellets were resuspended with 350mL/well of pre-chilled 90% methanol, and incubated at 4° C. for 30minutes. Plates were centrifuged at 300×g for 5 minutes, supernatantcontaining 90% methanol was aspirated, and cells were washed with 800mL/well of staining buffer. Cell pellets were resuspended in stainingbuffer containing anti-pSTAT4-AlexaFluor647 (1 to 150 dilution, 150mL/well), and incubated at room temperature in the dark overnight.

Samples were transferred to 96-well U-bottom plates and flow cytometricanalysis was performed on a FACSCalibur or LSRFortessa equipped with aHTS plate loader (BD Biosciences). The lymphocyte population was gatedfor histogram analysis of pSTAT4. Background fluorescence was definedusing unstimulated cells and a gate was placed at the foot of the peakto include ˜0.5% gated population. The histogram statistical analysiswas performed using CellQuest{dot over (O)} Pro version 5.2.1 (BDBiosciences) or FACSDiva version 6.2 (BD Biosciences) software. Relativefluorescence unit (RFU), which measures the level of phospho STAT4, wascalculated by multiplying the percent positive population and its meanfluorescence. Data from 11 compound concentrations (singlicate at eachconcentration) was normalized as a percentage of control based on theformula:

% of Control=100×(A−B)/(C−B)

where A is the RFU from wells containing compound and IL-12, B is theRFU from wells without IL-12 and compound (minimum fluorescence) and Cis the RFU from wells containing only IL-12 (maximum fluorescence).Inhibition curves and IC₅₀ values were determined using the Prismversion 5 software (GraphPad, La Jolla, Calif.).

TABLE II Human whole blood IL-12 Data. Example HWB IL-12 Number IC₅₀(nM) 1 162 3 203 7 41 19 28 20 50 23 34 25 59 27 86 30 46 32 130

What is claimed is:
 1. A compound having the structure (I):

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A, A′ and A″ are independently O, C═O, C—R′ or N—R″, where R′and R″ may independently be H, amino, —NR₇COR₆, COR⁶, —CONR₇R₈, C₁-C₆alkyl, or hydroxy(C₁-C₆ alkyl)-, and R″ may be present or absent, and ispresent where the rules of valency permit, and where not more than oneof A, A′ and A″ is O or C═O; R₀ and R are independently H, Br, Cl, F, orC₁-C₆ alkyl; R₁ is H, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl)-; R₂ isselected from the group consisting of H, C₁-C₆ alkyl-, C₁-C₆ alkoxy-,hydroxy(C₁-C₆ alkyl)-, phenyl(C₁-C₆ alkyl)-, formyl, heteroaryl,heterocyclic, —COR₆, —OCOR₆, —COOR₆, —NR₇COR₆, CONR₇R₈, and—(CH₂)_(n)—W, where W is cyano, hydroxy, C₃-C₈ cycloalkyl, —SO₂NR₇R₈,and —SO₂—R₉, where R₉ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, heteroaryl, orheterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, orheteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy,or C₁-C₆ alkyl; X is C—R₃ or N, where R₃ may be H or C₁-C₆ alkyl; R₄ andR₅ are independently H, amino, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl)-;R₆, R₇ and R₈ are each independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy(C₁-C₆alkyl) or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionally substitutedby halo, CN or hydroxy; or, R₇ and R₈ together with the atom bondedthereto form a 5- or 6-membered ring, said ring being optionallysubstituted by halo, hydroxy, CN, or C₁-C₆ alkyl; and, n is 0, 1, 2 or3.
 2. The compound of claim 1 having the structure (Ia):

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: A, A′ and A″ are independently O, C═O, C—R′ or N—R″, where R′and R″ may independently be H, amino, —NR₇COR₆, COR₆, —CONR₇R₈, C₁-C₆alkyl, or hydroxy(C₁-C₆ alkyl), and R″ may be present or absent, and ispresent where the rules of valency permit, and where not more than oneof A, A′ and A″ is O or C═O; R₀ and R are independently H, Br, Cl, F, orC₁-C₆ alkyl; R₁ is H, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl); R₂ isselected from the group consisting of H, 1-C₆ alkyl-, 1-C₆ alkoxy-,hydroxy(C₁-C₆ alkyl)-, phenyl(C₁-C₆ alkyl)-, formyl, heteroaryl,heterocyclic, —COR₆, —OCOR₆, —OCOR₆, —NR₇COR₆, —CONR₇R₈, and—(CH₂)_(n)—W, where W is cyano, hydroxy, C₃-C₈ cycloalkyl, —SO₂NR₇R₈,and —SO₂—R₉, where R₉ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, heteroaryl, orheterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, orheteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy,or 1-C₆ alkyl; R₃ may be H or 1-C₆ alkyl; R₄ and R₅ are independently H,amino, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl)-; R₆, R₇ and R₈ are eachindependently H, C₁-C₆ alkyl, C₁-C₄ alkoxy(C₁-C₆ alkyl)-, or C₃-C₈cycloalkyl, said C₁-C₆ alkyl is optionally substituted by halo, CN orhydroxy; or, R₇ and R₈ together with the atom bonded thereto form a 5-or 6-membered ring, said ring being optionally substituted by halo,hydroxy, CN, or C₁-C₆ alkyl; and, n is 0, 1, 2 or
 3. 3. The compound ofclaim 1 having the structure (Ib):

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: R″ is H, —COR₈, —CONR₇R₈, C₁-C₆ alkyl, or hydroxy(C₁-C₆alkyl)-; R₀ and R are independently H, Br, Cl, F, or C₁-C₆ alkyl; R₁ isH, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl); R₂ is selected from the groupconsisting of H, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy(C₁-C₆ alkyl),phenyl(C₁-C₆ alkyl), formyl, heteroaryl, heterocyclic, —COR₈, —OCOR₆,—COOR₈, —NR₇COR₈, —CONR₇R₈, and —(CH₂)_(n)—W, where W is cyano, hydroxy,C₃-C₈ cycloalkyl, —SO₂NR₇R₈, and —SO₂—R₉, where R₉ is 1-C₆ alkyl, C₃-C₈cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl,cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted orsubstituted by halo, cyano, hydroxy, or C₁-C₆ alkyl; R₃ may be H orC₁-C₆ alkyl; R₅ is independently H, amino, C₁-C₆ alkyl, or hydroxy(C₁-C₆alkyl); R₆, R₇ and R₈ are each independently H, C₁-C₆ alkyl, C₁-C₄alkoxy(C₁-C₆ alkyl), or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionallysubstituted by halo, CN or hydroxy; or, R₇ and R₈ together with the atombonded thereto form a 5- or 6-membered ring, said ring being optionallysubstituted by halo, hydroxy, CN, or C₁-C₆ alkyl; and, n is 0, 1, 2 or3.
 4. The compound of claim 3 wherein R″ is C₁-C₆ alkyl and R₅ is H. 5.The compound of claim 1 having the structure (Ic):

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: R″ is H, —COR₈, —CONR₇R₈, C₁-C₆ alkyl-, or hydroxy(C₁-C₆alkyl)-; R₂ is selected from the group consisting of H, C₁-C₆ alkyl,C₁-C₆ alkoxy-, hydroxy(C₁-C₆ alkyl)-, phenyl(C₁-C₆ alkyl-), formyl,heteroaryl, heterocyclic, —COR₆, —OCOR₆, —COOR₆, —NR₇COR₆, —CONR₇R₈, and—(CH₂)_(n)—W, where W is cyano, hydroxy, C₃-C₈ cycloalkyl, —SO₂NR₇R₈,and —SO₂—R₉, where R₉ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, heteroaryl, orheterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, orheteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy,or C₁-C₆ alkyl; R₃ is H, C₁-C₆ alkyl, amino, cyano, or C₁-C₆ alkoxy-; R₅is H, amino, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl)-; R₆, R₇ and R₈ areeach are each independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy(C₁-C₆ alkyl)-,or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionally substituted by halo,CN or hydroxy; or, R₇ and R₈ together with the atom bonded thereto forma 5- or 6-membered ring, said ring being optionally substituted by halo,hydroxy, CN, or C₁-C₆ alkyl; and, n is 0, 1, 2 or
 3. 6. The compound ofclaim 5 wherein R″ is C₁-C₆ alkyl and R₅ is H.
 7. The compound of claim1 having the structure (Id):

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: R″ is H, —COR₈, —CONR₇R₈, C₁-C₆ alkyl, or hydroxy(C₁-C₆alkyl)-; R₂ is selected from the group consisting of H, C₁-C₆ alkyl,C₁-C₆ alkoxy-, hydroxy(C₁-C₆ alkyl)-, phenyl(C₁-C₆ alkyl)-, formyl,heteroaryl, heterocyclic, —COR₈, —OCOR₈, —COOR₈, —CONR₇R₈, and—(CH₂)_(n)—W, where W is cyano, hydroxy, C₃-C₈ cycloalkyl-, —SO₂NR₇R₈,and —SO₂—R₉, where R₉ is C₁-C₈ alkyl, C₃-C₈ cycloalkyl, heteroaryl, orheterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, orheteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy,or C₁-C₆ alkyl; R₅ is H, amino, C₁-C₆ alkyl-, or hydroxy(C₁-C₆ alkyl)-;R₆, R₇ and R₈ are each are each independently H, C₁-C₆ alkyl, C₁-C₄alkoxy(C₁-C₆ alkyl), or C₃-C₈ cycloalkyl, said C₁-C₆ alkyl is optionallysubstituted by halo, CN or hydroxy; or, R₇ and R₈ together with the atombonded thereto form a 5- or 6-membered ring, said ring being optionallysubstituted by halo, hydroxy, CN, or C₁-C₆ alkyl; and, n is 0, 1, 2 or3.
 8. The compound of claim 7 wherein R″ is C₁-C₆ alkyl and R₅ is H. 9.The compound of claim 1 having the structure (le):

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: R₂ is selected from the group consisting of H, C₁-C₆ alkyl,C₁-C₆ alkoxy-, hydroxy(C₁-C₆ alkyl)-, phenyl(C₁-C₆ alkyl)-, formyl,heteroaryl, heterocyclic —COR⁶, —OCOR⁶, —COOR⁶, —CONR⁷R⁸, and—(CH₂)_(n)—W, where W is cyano, hydroxy, C₃-C₈ cycloalkyl, —SO₂NR⁷R⁸,and —SO₂—R⁹, where R⁹ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, heteroaryl, orheterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, orheteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy,or C₁-C₆ alkyl; R₆, R₇ and R₈ are each are each independently H, C₁-C₆alkyl, C₁-C₄ alkoxy(C₁-C₆ alkyl), or C₃-C₈ cycloalkyl, said C₁-C₆ alkylis optionally substituted by halo, CN or hydroxy; or, R₇ and R₈ togetherwith the atom bonded thereto form a 5- or 6-membered ring, said ringbeing optionally substituted by halo, hydroxy, CN, or C₁-C₆ alkyl; and,n is 0, 1, 2 or
 3. 10. The compound of claim 9 wherein R₂ is—(CH₂)_(n)—W, where W is cyano and n is 1, 2 or
 3. 11. The compound ofclaim 1 having the structure (If):

or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or pharmaceutically acceptable salt,wherein: R″ is H, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl)-; and, R₅ is H,amino, C₁-C₆ alkyl, or hydroxy(C₁-C₆ alkyl)-.
 12. The compound of claim11 wherein R″ is C₁-C₆ alkyl and R₅ is H.
 13. The compound of claim 1selected from the group consisting of:(1r,3r)-3-(4-(6-(3-amino-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile;2,2′-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1,3-diyl)diacetonitrile;2-((1s,3r)-1-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile;5-(4-(1-((1s,3r)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazole-3-carboxamide;(1s,3s)-3-(cyanomethyl)-3-(4-(6-(5-(hydroxymethyl)isoxazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile;(1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile;(1s,3s)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile;(1r,3r)-3-(cyanomethyl)-3-(4-(3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile; 2-((1r,3s)-1-(4-(6-(3-amino-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile;2-(1-ethyl-3-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile;(1r, 3r)-3-(Cyanomethyl)-3-(4-(6-(1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile(trans isomer); (1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-(hydroxymethyl)-1H-pyrazol-4-yl)pyrazolo[1, 5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile; and,or, a pharmaceutically acceptable salt thereof.
 14. The compound ofclaim 1 wherein the compound is(1r,3r)-3-(4-(6-(3-amino-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutane-1-carbonitrile,or a pharmaceutically acceptable salt thereof.
 15. The compound of claim1 wherein the compound is2,2′-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidine-1,3-diyl)diacetonitrile,or a pharmaceutically acceptable salt thereof.
 16. The compound of claim1 wherein the compound is24(1s,3r)-1-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile,or a pharmaceutically acceptable salt thereof.
 17. The compound of claim1 wherein the compound is5-(4-(14(1s,3r)-1-(cyanomethyl)-3-methoxycyclobutyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-6-yl)-1H-pyrazole-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 18. The compound of claim1 wherein the compound is(1s,3s)-3-(cyanomethyl)-3-(4-(6-(5-(hydroxymethyl)isoxazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile,or, a pharmaceutically acceptable salt thereof.
 19. The compound ofclaim 1 wherein the compound is(1r,3r)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile,or a pharmaceutically acceptable salt thereof.
 20. The compound of claim1 wherein the compound is(1s,3s)-3-(cyanomethyl)-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile,or a pharmaceutically acceptable salt thereof.
 21. The compound of claim1 wherein the compound is(1r,3r)-3-(cyanomethyl)-3-(4-(3-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile,or a pharmaceutically acceptable salt thereof.
 22. The compound of claim1 wherein the compound is24(1r,3s)-1-(4-(6-(3-amino-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-3-methoxycyclobutyl)acetonitrile,or a pharmaceutically acceptable salt thereof.
 23. The compound of claim1 wherein the compound is2-(1-ethyl-3-(4-(6-(5-(hydroxymethyl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile,or, a pharmaceutically acceptable salt thereof.
 24. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvate ofsaid compound or salt, and a pharmaceutically acceptable excipient. 25.A method of treating a disease or condition for which a Tyk2 inhibitoris indicated, in a subject in need of such treatment, comprisingadministering to the subject a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate of said compound or salt.
 26. Amethod of treating an inflammatory or autoimmune condition comprisingadministering to a subject suffering therefrom a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvate ofsaid compound or salt.
 27. A method of treating a disease or conditionselected from inflammation, autoimmune disease, systemic lupuserythematous, lupus nephritis, discoid lupus, cutaneous lupus, centralnervous system lupus, rheumatoid arthritis, psoriatic arthritis,inflammatory bowel disease, Crohn's disease, ulcerative colitis, asthma,allergic asthma, Type I diabetes, polymyositis, dermatomyositis, type Iinterferonopathies including AicardiGoutieres syndrome and othermendelian diseases of overexpression of type I interferon, multiplesclerosis, primary progressive multiple sclerosis, relapsing remittingmultiple sclerosis, primary biliary cirrhosis also known as primarybiliary cholangitis, primary sclerosing cholangitis, autoimmunehepatitis, non-alcoholic fatty liver disease, non-alcoholicsteatohepatitis, psoriasis, dermatomyositis, scleroderma, atopicdermatitis, vitiligo, alopecia areata, spondylopathy, ankylosingspondylitis, Alzheimer's disease, neuro-inflammation comprisingadministering to a subject suffering from said disease condition atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of said compound or salt.
 28. A method of treating asymptom of an autoimmune or inflammatory disease, comprisingadministering to a subject suffering therefrom a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutically acceptable solvate ofsaid compound or salt.
 29. The method of claim 28, wherein the symptomis selected from the group consisting of for example pruritis andfatigue.